Correlating multidimensional short-term empirical protein properties to long-term protein physical stability data via empirical phase diagrams

Klijn, Marieke E.; Hubbuch, Jürgen

doi:10.1016/j.ijpharm.2019.02.006

Cited by 5 publications

(1 citation statement)

References 54 publications

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“…Recent studies 2 , 44 , 50 , 51 have assessed the developability potential of a large set of antibodies using numerous high-throughput methods. None of these methods individually correlated with aggregation upon storage under different formulations, underlining the pressing need to combine multiple biophysical properties in one single aggregation propensity “score” to predict protein long-term stability against aggregation in an accurate manner.…”

Section: Introductionmentioning

confidence: 99%

An accelerated surface-mediated stress assay of antibody instability for developability studies

Kopp

Pérez

Zucca

et al. 2020

mAbs

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High physical stability is required for the development of monoclonal antibodies (mAbs) into successful therapeutic products. Developability assays are used to predict physical stability issues such as high viscosity and poor conformational stability, but protein aggregation remains a challenging property to predict. Among different types of stresses, air–water and solid–liquid interfaces are well known to potentially trigger protein instability and induce aggregation. Yet, in contrast to the increasing number of developability assays to evaluate bulk properties, there is still a lack of experimental methods to evaluate antibody stability against interfaces. Here, we investigate the potential of a hydrophobic nanoparticle surface-mediated stress assay to assess the stability of mAbs during the early stages of development. We evaluate this surface-mediated accelerated stability assay on a rationally designed library of 14 variants of a humanized IgG4, featuring a broad span of solubility values and other developability properties. The assay could identify variants characterized by high instability against agitation in the presence of air–water interfaces. Remarkably, for the set of investigated molecules, we observe strong correlations between the extent of aggregation induced by the surface-mediated stress assay and other developability properties of the molecules, such as aggregation upon storage at 45°C, self-association (evaluated by affinity-capture self-interaction nanoparticle spectroscopy) and nonspecific interactions (estimated by cross-interaction chromatography, stand-up monolayer chromatography (SMAC), SMAC*). This highly controlled surface-mediated stress assay has the potential to complement and increase the ability of the current set of screening techniques to assess protein aggregation and developability potential of mAbs during the early stages of drug development. Abbreviations :AC-SINS: Affinity-Capture Self-Interaction Nanoparticle Spectroscopy; AMS: Ammonium sulfate precipitation; ANS: 1-anilinonaphtalene-8-sulfonate; CIC: Cross-interaction chromatography; DLS: Dynamic light scattering; HIC: Hydrophobic interaction chromatography; HNSSA: Hydrophobic nanoparticles surface-stress assay; mAb: Monoclonal antibody; NP: Nanoparticle; SEC: Size exclusion chromatography; SMAC: Stand-up monolayer chromatography; WT: Wild type

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Section: Introductionmentioning

confidence: 99%

An accelerated surface-mediated stress assay of antibody instability for developability studies

Kopp

Pérez

Zucca

et al. 2020

mAbs

View full text Add to dashboard Cite

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Apparent protein cloud point temperature determination using a low volume high-throughput cryogenic device in combination with automated imaging

Klijn

Wöll

Hubbuch

2019

Bioprocess Biosyst Eng

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Relationship of PEG-induced precipitation with protein-protein interactions and aggregation rates of high concentration mAb formulations at 5 °C

Wälchli

Fanizzi

Massant

et al. 2020

European Journal of Pharmaceutics and Biopharmaceutics

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Correlating multidimensional short-term empirical protein properties to long-term protein physical stability data via empirical phase diagrams

Cited by 5 publications

References 54 publications

An accelerated surface-mediated stress assay of antibody instability for developability studies

An accelerated surface-mediated stress assay of antibody instability for developability studies

Apparent protein cloud point temperature determination using a low volume high-throughput cryogenic device in combination with automated imaging

Relationship of PEG-induced precipitation with protein-protein interactions and aggregation rates of high concentration mAb formulations at 5 °C

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Correlating multidimensional short-term empirical protein properties to long-term protein physical stability data via empirical phase diagrams

Cited by 5 publications

References 54 publications

An accelerated surface-mediated stress assay of antibody instability for developability studies

An accelerated surface-mediated stress assay of antibody instability for developability studies

Apparent protein cloud point temperature determination using a low volume high-throughput cryogenic device in combination with automated imaging

Relationship of PEG-induced precipitation with protein-protein interactions and aggregation rates of high concentration mAb formulations at 5 °C

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Relationship of PEG-induced precipitation with protein-protein interactions and aggregation rates of high concentration mAb formulations at 5 °C