| Added by | alainmange |
|---|---|
| Group name | PlateformePP2I |
| Item Type | Journal Article |
| Title | Harnessing Fc/FcRn Affinity Data from Patents with Different Machine Learning Methods |
| Creator | Dumet et al. |
| Author | Christophe Dumet |
| Author | Martine Pugnière |
| Author | Corinne Henriquet |
| Author | Valérie Gouilleux-Gruart |
| Author | Anne Poupon |
| Author | Hervé Watier |
| Abstract | Monoclonal antibodies are biopharmaceuticals with a very long half-life due to the binding of their Fc portion to the neonatal receptor (FcRn), a pharmacokinetic property that can be further improved through engineering of the Fc portion, as demonstrated by the approval of several new drugs. Many Fc variants with increased binding to FcRn have been found using different methods, such as structure-guided design, random mutagenesis, or a combination of both, and are described in the literature as well as in patents. Our hypothesis is that this material could be subjected to a machine learning approach in order to generate new variants with similar properties. We therefore compiled 1323 Fc variants affecting the affinity for FcRn, which were disclosed in twenty patents. These data were used to train several algorithms, with two different models, in order to predict the affinity for FcRn of new randomly generated Fc variants. To determine which algorithm was the most robust, we first assessed the correlation between measured and predicted affinity in a 10-fold cross-validation test. We then generated variants by in silico random mutagenesis and compared the prediction made by the different algorithms. As a final validation, we produced variants, not described in any patents, and compared the predicted affinity with the experimental binding affinities measured by surface plasmon resonance (SPR). The best mean absolute error (MAE) between predicted and experimental values was obtained with a support vector regressor (SVR) using six features and trained on 1251 examples. With this setting, the error on the log(KD) was less than 0.17. The obtained results show that such an approach could be used to find new variants with better half-life properties that are different from those already extensively used in therapeutic antibody development. |
| Publication | International Journal of Molecular Sciences |
| Volume | 24 |
| Issue | 6 |
| Pages | 5724 |
| Date | 2023-03-16 |
| Journal Abbr | Int J Mol Sci |
| Language | eng |
| DOI | 10.3390/ijms24065724 |
| ISSN | 1422-0067 |
| Library Catalog | PubMed |
| Extra | PMID: 36982796 PMCID: PMC10052518 |
| Tags | Antibodies, Monoclonal, antibody, author, Fc variant, FcRn, Histocompatibility Antigens Class I, Immunoglobulin Fc Fragments, Immunoglobulin G, machine learning, Mutagenesis, original, pp2i, Protein Binding, Receptors, Fc |
| Date Added | 2023/05/12 - 14:45:45 |
| Date Modified | 2023/05/12 - 14:46:03 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
