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ABSTRACT
In silico assessment of antibody developability during early lead candidate selection and optimization is of paramount importance, offering a rapid and material-free screening approach. However, the predictive power and reproducibility of such methods depend heavily on the selection of molecular descriptors, model parameters, accuracy of predicted structure models, and conformational sampling techniques. Here, we present a set of molecular surface descriptors specifically designed for predicting antibody developability. We assess the performance of these descriptors by benchmarking their correlations with an extensive array of experimentally determined biophysical properties, including viscosity, aggregation, hydrophobic interaction chromatography, human pharmacokinetic clearance, heparin retention time, and polyspecificity. Further, we investigate the sensitivity of these surface descriptors to methodological nuances, such as the choice of interior dielectric constant, hydrophobicity scales, structure prediction methods, and the impact of conformational sampling. Notably, we observe systematic shifts in the distribution of surface descriptors depending on the structure prediction method used, driving weak correlations of surface descriptors across structure models. Averaging the descriptor values over conformational distributions from molecular dynamics mitigates the systematic shifts and improves the consistency across different structure prediction methods, albeit with inconsistent improvements in correlations with biophysical data. Based on our benchmarking analysis, we propose six in silico developability risk flags and assess their effectiveness in predicting potential developability issues for a set of case study molecules.
Acknowledgments
The authors gratefully thank Bob Kelley, Jessie Zhao, Jonathan Zarzar, Trevor Swartz, Nandhini Rajagopal, Shrenik Mehta, Jasper Lin, and Darcy Davidson for their valuable comments and suggestions. The authors also thank Thomas Hoeffel, Joseph Lipscomb, and Kapil Bajaj for their assistance in running our simulations smoothly on our high-performance computing cluster.
Disclosure statement
All authors are current employees of Genentech, Inc, which develops and commercializes therapeutics, including antibodies.
Abbreviations
| AB2 | = | ABodyBuilder2 structure prediction tool |
| APBS | = | Adaptive Poisson-Boltzmann Solver |
| ASP | = | average surface property |
| BM | = | Black & Mould hydrophobicity scale |
| CST | = | clinical stage therapeutics |
| CDR | = | Antibody complementarity-determining region |
| CMC | = | chemistry, manufacturing, and controls stage |
| cMD | = | conventional Molecular Dynamics |
| EI | = | Eisenberg hydrophobicity scale |
| EP | = | electrostatic potential |
| ens_charge_Fv | = | ensemble charge of the Fv (MOE) |
| Fab | = | Fragment antigen-binding domain |
| Fv | = | Antibody variable domain |
| FvCSP | = | charge symmetry parameter (Sharma et al.) |
| GaMD | = | Gaussian-accelerated Molecular Dynamics |
| HIC | = | hydrophobic interaction chromatography |
| HI | = | Fv Hydrophobicity Index (Sharma et al.) |
| HPATCH | = | Hydropathy Patch |
| KD | = | Kyte-Doolittle hydrophobicity scale |
| KDE | = | kernel density estimate |
| mAbs | = | monoclonal antibodies |
| MD | = | Molecular Dynamics |
| MOE | = | Molecular Operating Environment software |
| MolDesk | = | Molecular Descriptors |
| OAS | = | Observed Antibody Space |
| PNC | = | Patches of Negative Charge (TAP) |
| PPC | = | Patches of Positive Charge (TAP) |
| PR-AUC | = | Precision-Recall Area Under Curve metric for binary classification |
| PSH | = | Protein Surface Hydrophobicity (TAP) |
| PSR | = | Poly-Specificity Reagent |
| pI_3D | = | structure-based PI (MOE) |
| PK | = | pharmacokinetic |
| RP-HPLC | = | reverse-phased high-performance liquid chromatography |
| RT | = | Retention time |
| SAP | = | Spatial Aggregation Propensity (Chennamsetty et al.) |
| SFvCSP | = | Surface-based charge symmetry parameter (TAP) |
| SCM | = | spatial charge map (Agrawal et al.) |
| SEC | = | size exclusion chromatography |
| SASA | = | solvent-accessible surface area |
| TAP | = | Therapeutic Antibody Profiler tool |
| WW | = | Wimley White hydrophobicity scale |
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2024.2362788