Structural Considerations in Affinity Maturation of Antibody-Based Biotherapeutic Candidates

Comeau, Stephen R.; Thorsteinson, Nels; Kumar, Sandeep

doi:10.1007/978-1-0716-2609-2_17

Cited by 2 publications

(3 citation statements)

References 24 publications

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“…Therefore, cocrystallized antibody-antigen complexes are typically preferred over structure-based homology models or AI predictions, which may lead to less reliable results if CDRs are not precisely modeled. The in silico affinity maturation relies on accurate molecular interactions for free energy or MM-GBSA-based calculations (Comeau et al, 2023;Thorsteinson et al, 2023), highlighting the importance of improving antibody-antigen complex predictions and the implicit incorporation of multiple conformational ensembles to enhance the effectiveness of in silico calculations and optimize library design. Despite this limitation, these methods have been already applied to predicted antibody-antigen complexes , facilitating the generation of in silico affinity maturation libraries (Conti et al, 2022;Thorsteinson et al, 2023).…”

Section: In Silico Affinity Maturation Of Lead Candidatesmentioning

confidence: 99%

Progress and challenges in computational structure-based design and development of biologic drugs

2024

Frontiers Research Topics

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Frontiers is more than just an open access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers journal seriesThe Frontiers journal series is a multi-tier and interdisciplinary set of openaccess, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. At the same time, the Frontiers journal series operates on a revolutionary invention, the tiered publishing system, initially addressing specific communities of scholars, and gradually climbing up to broader public understanding, thus serving the interests of the lay society, too. Dedication to qualityEach Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interactions between authors and review editors, who include some of the world's best academicians. Research must be certified by peers before entering a stream of knowledge that may eventually reach the public -and shape society; therefore, Frontiers only applies the most rigorous and unbiased reviews. Frontiers revolutionizes research publishing by freely delivering the most outstanding research, evaluated with no bias from both the academic and social point of view. By applying the most advanced information technologies, Frontiers is catapulting scholarly publishing into a new generation. What are Frontiers Research Topics?Frontiers Research Topics are very popular trademarks of the Frontiers journals series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area.

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Section: In Silico Affinity Maturation Of Lead Candidatesmentioning

confidence: 99%

Progress and challenges in computational structure-based design and development of biologic drugs

2024

Frontiers Research Topics

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“…Therefore, co-crystallized antibody–antigen complexes are typically preferred over structure-based homology models or AI predictions, which may lead to less reliable results if CDRs are not precisely modeled. The in silico affinity maturation relies on accurate molecular interactions for free energy or MM-GBSA–based calculations ( Comeau et al, 2023 ; Thorsteinson et al, 2023 ), highlighting the importance of improving antibody–antigen complex predictions and the implicit incorporation of multiple conformational ensembles to enhance the effectiveness of in silico calculations and optimize library design. Despite this limitation, these methods have been already applied to predicted antibody–antigen complexes ( Rangel et al, 2022 ), facilitating the generation of in silico affinity maturation libraries ( Conti et al, 2022 ; Thorsteinson et al, 2023 ).…”

Section: Opportunities For Computation At Various Stages Of Biotherap...mentioning

confidence: 99%

“…The subsequent challenge involves designing a combinatorial assembly of these mutations into a library suitable for phage/yeast display. This is because the in silico affinity maturation often involves computationally expensive calculations that tend to be more accurate at identifying the single point mutations rather than combinations thereof ( Comeau et al, 2023 ; Thorsteinson et al, 2023 ). The physical display libraries built using computational guidance can be used to pan combinatorial mutations.…”

Section: Opportunities For Computation At Various Stages Of Biotherap...mentioning

confidence: 99%

How can we discover developable antibody-based biotherapeutics?

Bauer,

Rajagopal,

Gupta

et al. 2023

Front. Mol. Biosci.

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Antibody-based biotherapeutics have emerged as a successful class of pharmaceuticals despite significant challenges and risks to their discovery and development. This review discusses the most frequently encountered hurdles in the research and development (R&D) of antibody-based biotherapeutics and proposes a conceptual framework called biopharmaceutical informatics. Our vision advocates for the syncretic use of computation and experimentation at every stage of biologic drug discovery, considering developability (manufacturability, safety, efficacy, and pharmacology) of potential drug candidates from the earliest stages of the drug discovery phase. The computational advances in recent years allow for more precise formulation of disease concepts, rapid identification, and validation of targets suitable for therapeutic intervention and discovery of potential biotherapeutics that can agonize or antagonize them. Furthermore, computational methods for de novo and epitope-specific antibody design are increasingly being developed, opening novel computationally driven opportunities for biologic drug discovery. Here, we review the opportunities and limitations of emerging computational approaches for optimizing antigens to generate robust immune responses, in silico generation of antibody sequences, discovery of potential antibody binders through virtual screening, assessment of hits, identification of lead drug candidates and their affinity maturation, and optimization for developability. The adoption of biopharmaceutical informatics across all aspects of drug discovery and development cycles should help bring affordable and effective biotherapeutics to patients more quickly.

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Structural Considerations in Affinity Maturation of Antibody-Based Biotherapeutic Candidates

Cited by 2 publications

References 24 publications

Progress and challenges in computational structure-based design and development of biologic drugs

Progress and challenges in computational structure-based design and development of biologic drugs

How can we discover developable antibody-based biotherapeutics?

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