PEP-Patch: Electrostatics in Protein-Protein Recognition, Specificity and Antibody Developability

Waibl, Franz; Pomarici, Nancy D; Hoerschinger, Valentin J; Loeffler, Johannes R.; Deane, Charlotte M.; Georges, Guy; Kettenberger, Hubert; Fernández‐Quintero, Monica L.; Liedl, Klaus R.

doi:10.1101/2023.07.14.547811

Cited by 2 publications

(1 citation statement)

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“…In fact, these interactions with hydrophobic surfaces can result in a population shift towards more hydrophobic conformations, which are more likely to aggregate. Thus, accounting for the high conformational diversity of antibodies by considering them as ensembles in solution can advance the antibody development process, as the identification of potential liabilities and optimization of biophysical properties, such as hydrophobicity and electrostatics, can be facilitated (Figure 1B) [66][67][68]. Because the antibody scaffold can recognize and accommodate diverse antigens with distinct motifs, Pauling and Landsteiner proposed in the 1940s that antibodies follow the concept of conformational diversity.…”

Section: Antibody Dynamicsmentioning

confidence: 99%

Structure and Dynamics Guiding Design of Antibody Therapeutics and Vaccines

Fernández-Quintero,

Pomarici,

Fischer

et al. 2023

Antibodies

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Antibodies and other new antibody-like formats have emerged as one of the most rapidly growing classes of biotherapeutic proteins. Understanding the structural features that drive antibody function and, consequently, their molecular recognition is critical for engineering antibodies. Here, we present the structural architecture of conventional IgG antibodies alongside other formats. We emphasize the importance of considering antibodies as conformational ensembles in solution instead of focusing on single-static structures because their functions and properties are strongly governed by their dynamic nature. Thus, in this review, we provide an overview of the unique structural and dynamic characteristics of antibodies with respect to their antigen recognition, biophysical properties, and effector functions. We highlight the numerous technical advances in antibody structure prediction and design, enabled by the vast number of experimentally determined high-quality structures recorded with cryo-EM, NMR, and X-ray crystallography. Lastly, we assess antibody and vaccine design strategies in the context of structure and dynamics.

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Section: Antibody Dynamicsmentioning

confidence: 99%

Structure and Dynamics Guiding Design of Antibody Therapeutics and Vaccines

Fernández-Quintero,

Pomarici,

Fischer

et al. 2023

Antibodies

Self Cite

View full text Add to dashboard Cite

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

Bashour,

Smorodina,

Pariset

et al. 2023

Preprint

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

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PEP-Patch: Electrostatics in Protein-Protein Recognition, Specificity and Antibody Developability

Cited by 2 publications

References 46 publications

Structure and Dynamics Guiding Design of Antibody Therapeutics and Vaccines

Structure and Dynamics Guiding Design of Antibody Therapeutics and Vaccines

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

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