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A Mechanistic Understanding of Monoclonal Antibody Interfacial Protection by Hydrolytically Degraded Polysorbate 20 and 80 under IV Bag Conditions

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Abstract

Purpose

Polysorbates (PS) contain polyoxyethylene (POE) sorbitan/isosorbide fatty acid esters that can partially hydrolyze over time in liquid drug products to generate degradants and a remaining intact PS fraction with a modified ester distribution. The degradants are composed of free fatty acids (FFAs) –-primarily lauric acid for PS20 and oleic acid for PS80–- and POE head groups. We previously demonstrated that under IV bag agitation conditions, mAb1 (a surface-active IgG4) aggregation increased with increasing amounts of degradants for PS20 but not for PS80. The purpose of this work is to understand the mechanism behind this observation.

Methods

The surface tension of the remaining intact PS fraction without degradants was modeled and compared with that of enzymatically degraded PS solutions. Next, mAb1 aggregation in saline was measured in the presence of laurate and oleate salts during static storage. Lastly, colloidal and conformational stability of mAb1 in the presence of these salts was investigated through differential scanning fluorimetry and dynamic light scattering under IV bag solution conditions.

Results

The surface tension was primarily influenced by FFAs rather than the modified ester distribution of the remaining intact PS. MAb1 bulk aggregation increased in the presence of laurate but not oleate salts. Both salt types increased the melting temperature of mAb1 indicating FFA-mAb1 interactions. However, only laurate salt increased mAb1 self-association potentially explaining the higher aggregation propensity in its presence.

Conclusion

Our results help explain the observed differences between hydrolytically degraded PS20 and PS80 in affecting mAb1 aggregation under IV bag agitation conditions.

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Acknowledgements

The authors would like to thank Inn Yuk, Sreedhara Alavattam, Jasper Lin and Jonathan Zarzar for feedback and discussions. The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Pharmaceutical Development, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Aadithya Kannan, Jamie Giddings, Shrenik Mehta, Tiffany Lin, Anthony Tomlinson, Kyle Ritchie, Ian Shieh, Miguel Saggu & Nidhi Doshi

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  1. Aadithya Kannan
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Correspondence to Nidhi Doshi.

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Kannan, A., Giddings, J., Mehta, S. et al. A Mechanistic Understanding of Monoclonal Antibody Interfacial Protection by Hydrolytically Degraded Polysorbate 20 and 80 under IV Bag Conditions. Pharm Res 39, 563–575 (2022). https://doi.org/10.1007/s11095-022-03217-x

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