Abstract
Monoclonal antibodies (mAbs) constitute a rapidly growing biopharmaceutical sector. However, their growth is impeded by high failure rates originating from failed clinical trials and developability issues in process development. There is, therefore, a growing need for better in silico tools to aid in risk assessment of mAb candidates to promote early-stage screening of potentially problematic mAb candidates. In this study, a quantitative structure–activity relationship (QSAR) modelling workflow was designed for the prediction of hydrophobic interaction chromatography (HIC) retention times of mAbs. Three novel descriptor sets derived from primary sequence, homology modelling, and atomistic molecular dynamics (MD) simulations were developed and assessed to determine the necessary level of structural resolution needed to accurately capture the relationship between mAb structures and HIC retention times. The results showed that descriptors derived from 3D structures obtained after MD simulations were the most suitable for HIC retention time prediction with a R2 = 0.63 in an external test set. It was found that when using homology modelling, the resulting 3D structures became biased towards the used structural template. Performing an MD simulation therefore proved to be a necessary post-processing step for the mAb structures in order to relax the structures and allow them to attain a more natural conformation. Based on the results, the proposed workflow in this paper could therefore potentially contribute to aid in risk assessment of mAb candidates in early development.
Highlights
Monoclonal antibodies have gained increasing popularity over the last three decades in terms of both sales and research investments due to their high specificity and clinical safety
quantitative structure–activity relationship (QSAR) models can serve as important in silico tools that allow for the prediction of Monoclonal antibodies (mAbs) behaviour concerning nonspecific interaction
A comparison between three descriptors sets (Seq2D, Hom3D, and MD3D) was performed and their applicability evaluated towards the prediction of antibody hydrophobic interaction chromatography (HIC) retention times (RT)
Summary
Monoclonal antibodies (mAbs) have gained increasing popularity over the last three decades in terms of both sales and research investments due to their high specificity and clinical safety. Over 550 antibody candidates are currently being reviewed in early clinical trials (Stage I and Stage II) as well as 79 candidates in late-stage development which makes the antibody therapeutics one of the fastest growing segments in the pharmaceutical market [4] Due to their popularity, biopharmaceutical companies invest several billions of dollars in development for every new mAb candidate, which was estimated to be $2.558 billion on average from start to finish in 2016 [5]. Selection criteria of lead candidates in the preclinical phase are today mainly based on drug specificity, affinity, and potency towards a target antigen, whereas properties related to clinical safety and product quality are generally not thoroughly explored. Considering the large investments in the pre-clinical phase alone, which were estimated to $1.098 billion, a robust assessment of an antibodies developability is sorely needed to further characterise antibody properties related to clinical safety and manufacturability in order to decrease failure rates and attrition in biopharma [5,7]
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