Biophysical cartography of the native and human-engineered antibody landscapes quantifies the plasticity of antibody developability

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: July 31, 2024

Designing effective monoclonal antibody (mAb) therapeutics faces a multi-parameter optimization challenge known as "developability", which reflects an antibody's ability to progress through development stages based on its physicochemical properties. While natural antibodies may provide valuable guidance for mAb selection, we lack comprehensive understanding of developability parameter (DP) plasticity (redundancy, predictability, sensitivity) and how the DP landscapes human-engineered relate one another. These gaps hinder fundamental profile cartography. To chart engineered landscapes, computed 40 sequence- 46 structure-based DPs over two million native single-chain sequences. We find lower redundancy among compared sequence-based DPs. Sequence sensitivity single amino acid substitutions varied by region DP, structure values across conformational ensemble structures. show that sequence are more predictable than ones different machine-learning tasks embeddings, indicating constrained design space. Human-engineered localize within antibodies, suggesting explore mere subspaces one. Our work quantifies developability, providing resource therapeutic design. Analysis 2 reveals form This large-scale analysis allows quantification plasticity, accelerating drug

Language: Английский

Biophysical cartography of the native and human-engineered antibody landscapes quantifies the plasticity of antibody developability

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 30, 2023

Abstract Designing effective monoclonal antibody (mAb) therapeutics faces a multi-parameter optimization challenge known as “developability”, which reflects an antibody’s ability to progress through development stages based on its physicochemical properties. While natural antibodies may provide valuable guidance for mAb selection, we lack comprehensive understanding of developability parameter (DP) plasticity (redundancy, predictability, sensitivity) and how the DP landscapes human-engineered relate one another. These gaps hinder fundamental profile cartography. To chart engineered landscapes, computed 40 sequence- 46 structure-based DPs over two million native single-chain sequences. We found lower redundancy among compared sequence-based DPs. Sequence sensitivity single amino acid substitutions varied by region DP, structure values across conformational ensemble structures. were more predictable than ones different machine-learning tasks embeddings, indicating constrained design space. Human-engineered localized within sequence antibodies, suggesting that explore mere subspaces one. Our work quantifies developability, providing resource therapeutic design.

Language: Английский

Probing the Protein–Excipient Interaction in the Orally Delivered Protein by Solid-State Hydrogen–Deuterium Exchange Mass Spectrometry and Molecular Dynamics

Analytical Chemistry, Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 28, 2023

The oral administration of protein therapeutics in solid dosage form is gaining popularity due to its benefits, such as improved medication adherence, convenience, and ease use for patients compared traditional parental delivery. However, formulating biologics presents challenges related pH barriers, enzymatic breakdown, poor bioavailability. Therefore, understanding the interaction between excipients state crucial formulation development. In this Letter, we present a case study focused on investigating role aggregation during production single variable domain heavy chain (VHH) protein. We employed solid-state hydrogen–deuterium exchange coupled with mass spectrometry (ssHDX-MS) at both intact peptide levels assess differences protein–excipient interactions two formulations. ssHDX-MS analysis revealed that one effectively prevents compaction by blocking β-sheets across VHH protein, thereby preventing β-sheet−β-sheet interactions. Spatial propensity (SAP) mapping cosolvent simulation from molecular dynamics (MD) further validated sites identified through ssHDX-MS. Additionally, MD demonstrated involves hydrophilic and/or hydrogen bonding. This novel approach holds significant potential can guide process development orally delivered forms, ultimately enhancing their efficacy stability.

Language: Английский