LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies.
Antibody-based therapeutics must not undergo chemical modifications that would impair their efficacy or hinder their developability. A commonly used technique to de-risk lead biotherapeutic candidates annotates chemical liability motifs on their sequence. By analyzing sequences from all major source...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-03-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011881&type=printable |
| _version_ | 1797238497171472384 |
|---|---|
| author | Tadeusz Satława Mateusz Tarkowski Sonia Wróbel Paweł Dudzic Tomasz Gawłowski Tomasz Klaus Marek Orłowski Anna Kostyn Sandeep Kumar Andrew Buchanan Konrad Krawczyk |
| author_facet | Tadeusz Satława Mateusz Tarkowski Sonia Wróbel Paweł Dudzic Tomasz Gawłowski Tomasz Klaus Marek Orłowski Anna Kostyn Sandeep Kumar Andrew Buchanan Konrad Krawczyk |
| author_sort | Tadeusz Satława |
| collection | DOAJ |
| description | Antibody-based therapeutics must not undergo chemical modifications that would impair their efficacy or hinder their developability. A commonly used technique to de-risk lead biotherapeutic candidates annotates chemical liability motifs on their sequence. By analyzing sequences from all major sources of data (therapeutics, patents, GenBank, literature, and next-generation sequencing outputs), we find that almost all antibodies contain an average of 3-4 such liability motifs in their paratopes, irrespective of the source dataset. This is in line with the common wisdom that liability motif annotation is over-predictive. Therefore, we have compiled three computational flags to prioritize liability motifs for removal from lead drug candidates: 1. germline, to reflect naturally occurring motifs, 2. therapeutic, reflecting chemical liability motifs found in therapeutic antibodies, and 3. surface, indicative of structural accessibility for chemical modification. We show that these flags annotate approximately 60% of liability motifs as benign, that is, the flagged liabilities have a smaller probability of undergoing degradation as benchmarked on two experimental datasets covering deamidation, isomerization, and oxidation. We combined the liability detection and flags into a tool called Liability Antibody Profiler (LAP), publicly available at lap.naturalantibody.com. We anticipate that LAP will save time and effort in de-risking therapeutic molecules. |
| first_indexed | 2024-04-24T17:36:35Z |
| format | Article |
| id | doaj.art-cff3dcbea5874d0a8c29f6bd8aadeb8d |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-24T17:36:35Z |
| publishDate | 2024-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-cff3dcbea5874d0a8c29f6bd8aadeb8d2024-03-28T05:32:35ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582024-03-01203e101188110.1371/journal.pcbi.1011881LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies.Tadeusz SatławaMateusz TarkowskiSonia WróbelPaweł DudzicTomasz GawłowskiTomasz KlausMarek OrłowskiAnna KostynSandeep KumarAndrew BuchananKonrad KrawczykAntibody-based therapeutics must not undergo chemical modifications that would impair their efficacy or hinder their developability. A commonly used technique to de-risk lead biotherapeutic candidates annotates chemical liability motifs on their sequence. By analyzing sequences from all major sources of data (therapeutics, patents, GenBank, literature, and next-generation sequencing outputs), we find that almost all antibodies contain an average of 3-4 such liability motifs in their paratopes, irrespective of the source dataset. This is in line with the common wisdom that liability motif annotation is over-predictive. Therefore, we have compiled three computational flags to prioritize liability motifs for removal from lead drug candidates: 1. germline, to reflect naturally occurring motifs, 2. therapeutic, reflecting chemical liability motifs found in therapeutic antibodies, and 3. surface, indicative of structural accessibility for chemical modification. We show that these flags annotate approximately 60% of liability motifs as benign, that is, the flagged liabilities have a smaller probability of undergoing degradation as benchmarked on two experimental datasets covering deamidation, isomerization, and oxidation. We combined the liability detection and flags into a tool called Liability Antibody Profiler (LAP), publicly available at lap.naturalantibody.com. We anticipate that LAP will save time and effort in de-risking therapeutic molecules.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011881&type=printable |
| spellingShingle | Tadeusz Satława Mateusz Tarkowski Sonia Wróbel Paweł Dudzic Tomasz Gawłowski Tomasz Klaus Marek Orłowski Anna Kostyn Sandeep Kumar Andrew Buchanan Konrad Krawczyk LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies. PLoS Computational Biology |
| title | LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies. |
| title_full | LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies. |
| title_fullStr | LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies. |
| title_full_unstemmed | LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies. |
| title_short | LAP: Liability Antibody Profiler by sequence & structural mapping of natural and therapeutic antibodies. |
| title_sort | lap liability antibody profiler by sequence structural mapping of natural and therapeutic antibodies |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1011881&type=printable |
| work_keys_str_mv | AT tadeuszsatława lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT mateusztarkowski lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT soniawrobel lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT pawełdudzic lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT tomaszgawłowski lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT tomaszklaus lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT marekorłowski lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT annakostyn lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT sandeepkumar lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT andrewbuchanan lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies AT konradkrawczyk lapliabilityantibodyprofilerbysequencestructuralmappingofnaturalandtherapeuticantibodies |