Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling
Abstract Antibodies with lambda light chains (λ-antibodies) are generally considered to be less developable than those with kappa light chains (κ-antibodies). Though this hypothesis has not been formally established, it has led to substantial systematic biases in drug discovery pipelines and thus co...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
|
| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05744-8 |
| _version_ | 1827381990280658944 |
|---|---|
| author | Matthew I. J. Raybould Oliver M. Turnbull Annabel Suter Bora Guloglu Charlotte M. Deane |
| author_facet | Matthew I. J. Raybould Oliver M. Turnbull Annabel Suter Bora Guloglu Charlotte M. Deane |
| author_sort | Matthew I. J. Raybould |
| collection | DOAJ |
| description | Abstract Antibodies with lambda light chains (λ-antibodies) are generally considered to be less developable than those with kappa light chains (κ-antibodies). Though this hypothesis has not been formally established, it has led to substantial systematic biases in drug discovery pipelines and thus contributed to kappa dominance amongst clinical-stage therapeutics. However, the identification of increasing numbers of epitopes preferentially engaged by λ-antibodies shows there is a functional cost to neglecting to consider them as potential lead candidates. Here, we update our Therapeutic Antibody Profiler (TAP) tool to use the latest data and machine learning-based structure prediction, and apply it to evaluate developability risk profiles for κ-antibodies and λ-antibodies based on their surface physicochemical properties. We find that while human λ-antibodies on average have a higher risk of developability issues than κ-antibodies, a sizeable proportion are assigned lower-risk profiles by TAP and should represent more tractable candidates for therapeutic development. Through a comparative analysis of the low- and high-risk populations, we highlight opportunities for strategic design that TAP suggests would enrich for more developable λ-antibodies. Overall, we provide context to the differing developability of κ- and λ-antibodies, enabling a rational approach to incorporate more diversity into the initial pool of immunotherapeutic candidates. |
| first_indexed | 2024-03-08T14:12:59Z |
| format | Article |
| id | doaj.art-3aa009e08b094dc2937b78da4414d5a3 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-08T14:12:59Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-3aa009e08b094dc2937b78da4414d5a32024-01-14T12:33:03ZengNature PortfolioCommunications Biology2399-36422024-01-017111310.1038/s42003-023-05744-8Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profilingMatthew I. J. Raybould0Oliver M. Turnbull1Annabel Suter2Bora Guloglu3Charlotte M. Deane4Oxford Protein Informatics Group, Department of Statistics, University of OxfordOxford Protein Informatics Group, Department of Statistics, University of OxfordOxford Protein Informatics Group, Department of Statistics, University of OxfordOxford Protein Informatics Group, Department of Statistics, University of OxfordOxford Protein Informatics Group, Department of Statistics, University of OxfordAbstract Antibodies with lambda light chains (λ-antibodies) are generally considered to be less developable than those with kappa light chains (κ-antibodies). Though this hypothesis has not been formally established, it has led to substantial systematic biases in drug discovery pipelines and thus contributed to kappa dominance amongst clinical-stage therapeutics. However, the identification of increasing numbers of epitopes preferentially engaged by λ-antibodies shows there is a functional cost to neglecting to consider them as potential lead candidates. Here, we update our Therapeutic Antibody Profiler (TAP) tool to use the latest data and machine learning-based structure prediction, and apply it to evaluate developability risk profiles for κ-antibodies and λ-antibodies based on their surface physicochemical properties. We find that while human λ-antibodies on average have a higher risk of developability issues than κ-antibodies, a sizeable proportion are assigned lower-risk profiles by TAP and should represent more tractable candidates for therapeutic development. Through a comparative analysis of the low- and high-risk populations, we highlight opportunities for strategic design that TAP suggests would enrich for more developable λ-antibodies. Overall, we provide context to the differing developability of κ- and λ-antibodies, enabling a rational approach to incorporate more diversity into the initial pool of immunotherapeutic candidates.https://doi.org/10.1038/s42003-023-05744-8 |
| spellingShingle | Matthew I. J. Raybould Oliver M. Turnbull Annabel Suter Bora Guloglu Charlotte M. Deane Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling Communications Biology |
| title | Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling |
| title_full | Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling |
| title_fullStr | Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling |
| title_full_unstemmed | Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling |
| title_short | Contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling |
| title_sort | contextualising the developability risk of antibodies with lambda light chains using enhanced therapeutic antibody profiling |
| url | https://doi.org/10.1038/s42003-023-05744-8 |
| work_keys_str_mv | AT matthewijraybould contextualisingthedevelopabilityriskofantibodieswithlambdalightchainsusingenhancedtherapeuticantibodyprofiling AT olivermturnbull contextualisingthedevelopabilityriskofantibodieswithlambdalightchainsusingenhancedtherapeuticantibodyprofiling AT annabelsuter contextualisingthedevelopabilityriskofantibodieswithlambdalightchainsusingenhancedtherapeuticantibodyprofiling AT boraguloglu contextualisingthedevelopabilityriskofantibodieswithlambdalightchainsusingenhancedtherapeuticantibodyprofiling AT charlottemdeane contextualisingthedevelopabilityriskofantibodieswithlambdalightchainsusingenhancedtherapeuticantibodyprofiling |