Beyond Antibodies: Engineered Protein Scaffolds for Therapeutic Development

Mehta, Nishant; Cochran, Jennifer R.

doi:10.1002/9783527699124.ch6

Cited by 2 publications

(1 citation statement)

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“…However, while classical IgG-based therapeutics gave rise to the majority of approved biopharmaceutics on the market, the emerging R&D pipelines are fueled by innovative formats such as bispecifics and small protein scaffolds (Löfblom et al, 2011; Mehta & Cochran, 2017). Here, much less experimental data is available to feed predictive models.…”

Section: Introductionmentioning

confidence: 99%

Holistic in silico developability assessment of novel classes of small proteins using publicly available sequence-based predictors

Pais,

Mayer,

Felderer

et al. 2023

Preprint

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The development of novel therapeutic proteins is a lengthy and costly process, with an average attrition rate of 91% (Thomas et al., 2021). To increase the probability of success and ensure robust drug supply beyond approval, it is essential to assess the developability profile of new potential drug candidates as early and broadly as possible in development (Jain et al., 2023). Predicting these propertiesin silicois expected to be the next leap in innovation as it would enable significantly reduced development timelines combined with broader screens at lower costs. However, developing predictive algorithms typically requires substantial datasets generated under very defined conditions, a limiting factor especially for new classes of therapeutic proteins that hold immense clinical promise.Here we describe a strategy for assessing the developability of a novel class of small therapeutic Anticalin® proteins using machine learning in conjunction with a knowledge-driven approach. The knowledge-driven approach considers developability attributes such as aggregation propensity, charge variants, immunogenicity, specificity, thermal stability, hydrophobicity, and potential post-translational modifications, to calculate a holistic developability score. Based on sequence-derived descriptors as input parameters we established novel statistical models designed to predict the developability scores for Anticalin proteins. The best models yielded low root mean square errors across the entire dataset and were further validated by removing input data from individual screening campaigns and predicting developability scores for those drug candidates.The adoption of the described workflow will enable significantly streamlined preclinical development of Anticalin drug candidates and could potentially be applied to other therapeutic protein scaffolds.

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Section: Introductionmentioning

confidence: 99%