2016
DOI: 10.1080/19420862.2016.1189048
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A comparison of biophysical characterization techniques in predicting monoclonal antibody stability

Abstract: With the rapid growth of biopharmaceutical product development, knowledge of therapeutic protein stability has become increasingly important. We evaluated assays that measure solution-mediated interactions and key molecular characteristics of 9 formulated monoclonal antibody (mAb) therapeutics, to predict their stability behavior. Colloidal interactions, self-association propensity and conformational stability were measured using effective surface charge via zeta potential, diffusion interaction parameter (k D… Show more

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Cited by 103 publications
(69 citation statements)
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References 41 publications
(51 reference statements)
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“…These results imply that despite exhibiting lower T onset for conformational changes at pH 5.8, Fab aggregates less at pH 5.8 compared to pH 8.0, indicating that the colloidal stability is playing a major role in Fab aggregation. These results are quite consistent with recent studies which indicated that the colloidal stability can account for the lack of a clear relationship between the conformational stability and aggregation of mAbs 49,50 .…”
Section: Resultssupporting
confidence: 93%
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“…These results imply that despite exhibiting lower T onset for conformational changes at pH 5.8, Fab aggregates less at pH 5.8 compared to pH 8.0, indicating that the colloidal stability is playing a major role in Fab aggregation. These results are quite consistent with recent studies which indicated that the colloidal stability can account for the lack of a clear relationship between the conformational stability and aggregation of mAbs 49,50 .…”
Section: Resultssupporting
confidence: 93%
“…Similar results have been observed in two other published studies. In the first study on the aggregation behavior of ten different IgG1 antibodies 49 , there was no absolute trend between the conformational stability and aggregation of the IgG1 molecules, implying that colloidal stability plays a major role in IgG1 aggregation. In the second study 50 , changing the solution pH from 6.5 to 4.5 reduced the thermal stability of IgG1; however, less protein aggregation was observed at pH 4.5, because of the increased colloidal stability of the protein.…”
Section: Discussionmentioning
confidence: 99%
“…300 Several methods exist for assessing the conformational stability and aggregation propensity of drug candidates, as well as related properties such as colloidal stability and self-association. 132,312,313 Stress tests attempt to quickly predict the long-term stability of proteins by exposing them to conditions that allow for exploration of nonnative conformations. In principle, aggregation can be accelerated by increasing the free energy of the native state, decreasing the free energy of the unfolded state, or adding energy to the system to overcome kinetic barriers between states.…”
Section: Stability and Aggregationmentioning
confidence: 99%
“…Recently, the ability of thermal unfolding assays to predict physical stability has been questioned, with properties such as self-association, colloidal stability, and chemical denaturation stability being proposed as superior predictive parameters than melting temperature. 313,315 Tryptophan fluorescence is another property potentially correlated to total monomer loss (fragmentation plus aggregation) rather than aggregation alone. 313 The presence of aggregationprone regions may also be predicted using sequence-based computational modeling approaches.…”
Section: Stability and Aggregationmentioning
confidence: 99%
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