Predicting Antibody Developability Profiles Through Early Stage Discovery Screening

Abstract

Monoclonal antibodies play an increasingly important role for the development of new drugs across multiple therapy areas. The term 'developability' encompasses the feasibility of molecules to successfully progress from discovery to development via evaluation of their physicochemical properties. These properties include the tendency for self-interaction and aggregation, thermal stability, colloidal stability, and optimization of their properties through sequence engineering. Selection of the best antibody molecule based on biological function, efficacy, safety, and developability allows for a streamlined and successful CMC phase. An efficient and practical high-throughput developability workflow (100 s-1,000 s of molecules) implemented during early antibody generation and screening is crucial to select the best lead candidates. This involves careful assessment of critical developability parameters, combined with binding affinity and biological properties evaluation using small amounts of purified material (<1 mg), as well as an efficient data management and database system. Herein, a panel of 152 various human or humanized monoclonal antibodies was analyzed in biophysical property assays. Correlations between assays for different sets of properties were established. We demonstrated in two case studies that physicochemical properties and key assay endpoints correlate with key downstream process parameters. The workflow allows the elimination of antibodies with suboptimal properties and a rank ordering of molecules for further evaluation early in the candidate selection process. This enables any further engineering for problematic sequence attributes without affecting program timelines.

Technology outlook for real‐time quality attribute and process parameter monitoring in biopharmaceutical development—A review

“…Biotherapeutic manufacturers are keen to generate higher titers with high concentrations at the drug product stage as a part of process intensification (J. Xu et al, 2020). However, highly concentrated formulations are more susceptible to biomolecular aggregation, leading to highly turbid and viscous solutions (Bailly et al, 2020). The concentration measurements in turbid, high concentration drug products by traditional UV spectroscopic techniques is challenging due to scattering effects.…”

“…As cavity absorbance spectrometry does not require any chemometric modeling or advanced data analytics as opposed to mid‐IR or Raman techniques, it could be a promising and simple technology to use as a PAT tool for protein concentration measurements in turbid solutions. High concentration formulations also lead to subvisible particle generation especially in the drug product stage (Bailly et al, 2020). Light scattering and image analysis techniques, such as dynamic light scattering, static light scattering, and FlowCAM® are some of the well‐known techniques for offline particle size and shape analysis (Corvari et al, 2015).…”

Toward Drug-Like Multispecific Antibodies by Design

“…As advances in assays for aggregation have improved, so too have high-throughput methods for analyzing aggregation propensity early in development [ 92 , 115 ]. Two particularly notable studies have sought correlations between early-stage analyses of biophysical parameters and late-stage developability [ 116 , 117 ]. In the first study, the results of twelve different biophysical assays for 137 antibodies that had advanced to at least phase II clinical studies were analyzed [ 116 ].…”

“…In the second related study, the results of a largely different set of early-stage biophysical assays for 152 human or humanized monoclonal antibodies were evaluated for correlations between early-stage screening results and downstream developmental parameters [ 117 ]. The authors observed a significant number of correlations between early-stage high-throughput assays and later stage analytical methods that often require much more sample.…”

“…Furthermore, high melting and aggregation temperatures were correlated with the best colloidal properties. Using a strategy based largely around early-stage optimization of aggregation behavior, an antibody with a substantially improved developability profile was produced, suggesting that measurements of melting and aggregation temperatures are indeed useful early surrogates for predicting and optimizing some late-stage developability parameters of antibodies [ 117 ]. While these findings may have important implications for multispecific antibodies, it is not known if the same correlations apply to such non-traditional formats.…”