On the role of salt type and concentration on the stability behavior of a monoclonal antibody solution

Arosio, Paolo; Jaquet, Baptiste; Wu, Hua; Morbidelli, Massimo

doi:10.1016/j.bpc.2012.05.004

Cited by 81 publications

(70 citation statements)

References 55 publications

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“…Indeed, it is difficult to alter the parallel assembly, powered by the stable registration of positive N termini on negative mica surface cavities, for the first layer (25). This also supports previous views (20)(21)(22)32) that peptide self-assembly is strongly influenced by its microenvironment. Even with the same bulk salt solution, parallel assembly was favored for the first layer (due to the attractive interaction with the mica surface), whereas the antiparallel assembly was favored for the second layer.…”

Section: Resultssupporting

confidence: 86%

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Dai

Kang

Huynh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Surface-assisted self-assembly of amyloid-like peptides has received considerable interest in both amyloidosis research and nanotechnology in recent years. Despite extensive studies, some controlling factors, such as salts, are still not well understood, even though it is known that some salts can promote peptide selfassemblies through the so-called "salting-out" effect. However, they are usually noncontrollable, disordered, amorphous aggregates. Here, we show via a combined experimental and theoretical approach that a conserved consensus peptide NH 2 -VGGAVVAGV-CONH 2 (GAV-9) (from representative amyloidogenic proteins) can self-assemble into highly ordered, multilayered nanofilaments, with surprising all-upright conformations, under high-salt concentrations. Our atomic force microscopy images also demonstrate that the vertical stacking of multiple layers is highly controllable by tuning the ionic strength, such as from 0 mM (monolayer) to 100 mM (mainly double layer), and to 250 mM MgCl 2 (double, triple, quadruple, and quintuple layers). Our atomistic molecular dynamics simulations then reveal that these individual layers have very different internal nanostructures, with parallel β-sheets in the first monolayer but antiparallel β-sheets in the subsequent upper layers due to their different microenvironment. Further studies show that the growth of multilayered, all-upright nanostructures is a common phenomenon for GAV-9 at the mica/water interface, under a variety of salt types and a wide range of salt concentrations.amyloid peptide | atomic force microscopy | salt effect | self-assembly on mica A better understanding of the self-assembly of highly ordered peptide nanostructures is critical because it not only helps to uncover the pathogenesis of various neurodegenerative diseases (1) but provides an attractive "bottom-up" nanotechnology for de novo nanodevice design (2) and fabrication (3). In addition to a series of factors (4-6) previously discovered to modulate peptide self-assembly, solid substrates have been found to drive this process directly acting as templates (7,8), controlling both assembly kinetics and morphology of amyloid peptide aggregates (8-11). These findings emphasize the importance of the substrate surface, whether it be a cellular membrane or an inorganic solid surface, on the assembly of various peptides, which is critical in many biological processes. It has been shown recently that fibrous nanostructures form a fundamental framework ubiquitous in normal cellular metabolism, including cell division and signaling, as well as in over 27 different human amyloid diseases and 9 in animals (12).Due to the complexity of cellular membranes and associated physiological conditions (13,14), hydrophilic mica and hydrophobic highly oriented pyrolytic graphite (HOPG) are the two commonly used model substrates for the investigation of surface effects (10,11,15). For example, it was found that amyloid-β (Aβ) peptide formed oligomeric protofibrillar aggregates on mica but only 1D nanofilaments on HOPG (...

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Section: Resultssupporting

confidence: 86%

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Dai

Kang

Huynh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…18,19 Upon formation of aggregates of various size and shape, these aggregation-prone areas are shielded from the aqueous environment by inter-molecular interactions between monomer molecules. 15,20 Dimeric forms of IgG molecules and mAbs have been described previously in literature. Recently, dimers of IgG1 and IgG2 have been found to occur naturally in human serum, although in low amounts.…”

Section: Introductionmentioning

confidence: 99%

Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs

Plath

Ringler

Graff-Meyer

et al. 2016

mAbs

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(2016) Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs, mAbs, 8:5, 928-940, DOI: 10.1080/19420862.2016 To link to this article: https://doi.org/10. 1080/19420862.2016 ABSTRACTThe formation of undesired high molecular weight species such as dimers is an important quality attribute for therapeutic monoclonal antibody formulations. Therefore, the thorough understanding of mAb dimerization and the detailed characterization mAb dimers is of great interest for future pharmaceutical development of therapeutic antibodies. In this work, we focused on the analyses of different mAb dimers regarding size, surface properties, chemical identity, overall structure and localization of possible dimerization sites. Dimer fractions of different mAbs were isolated to a satisfactory purity from bulk material and revealed 2 predominant overall structures, namely elongated and compact dimer forms. The elongated dimers displayed one dimerization site involving the tip of the Fab domain. Depending on the stress applied, these elongated dimers are connected either covalently or non-covalently. In contrast, the compact dimers exhibited non-covalent association. Several interaction points were detected for the compact dimers involving the hinge region or the base of the Fab domain. These results indicate that mAb dimer fractions are rather complex and may contain more than one kind of dimer. Nevertheless, the overall appearance of mAb dimers suggests the existence of 2 predominant dimeric structures, elongated and compact, which are commonly present in preparations of therapeutic mAbs.

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“…While the protein colloidal stability depends mainly on intermolecular protein-protein interactions, the protein conformational stability is dictated by the delicate balance between solvation and intramolecular protein interactions. The protein colloidal stability and the protein conformational stability are highly sensitive to the solution composition and are strongly interconnected [40]. For instance, denaturing conditions promote the exposure of buried hydrophobic patches upon protein unfolding, which then leads to additional strong attractive hydrophobic intermolecular interactions favoring aggregation.…”

Section: Colloidal Stability and Conformational Stabilitymentioning

confidence: 99%

“…In addition to the aforementioned forces, a variety of non-DLVO forces such as hydration forces, hydrophobic forces, and hydrogen bonding often play a prominent role in protein stability [40][41][42]. Moreover, the protein surface patchiness tends to increase the colloidal stability of proteins in solution as compared to the case of traditional colloids [43].…”

Section: Second Virial Coefficient To Quantify the Protein Colloidal mentioning

confidence: 99%

A multiscale view of therapeutic protein aggregation: A colloid science perspective

Nicoud

Owczarz

Arosio

et al. 2015

Biotechnology Journal

Self Cite

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The formation of aggregates in protein-based pharmaceuticals is a major issue that can compromise drug safety and drug efficacy. With a view to improving protein stability, considerable effort is put forth to unravel the fundamental mechanisms underlying the aggregation process. However, therapeutic protein aggregation is a complex multistep phenomenon that involves time and length scales spanning several orders of magnitude, and strategies addressing protein aggregation inhibition are currently still largely empirical in practice. Here, we review how key concepts developed in the frame of colloid science can be applied to gain knowledge on the kinetics and thermodynamics of therapeutic protein aggregation across different length scales. In particular, we discuss the use of coarse-grained molecular interaction potentials to quantify protein colloidal stability. We then show how population balance equations simulations can provide insights into the mechanisms of aggregate formation at the mesoscale, and we highlight the strength of the concept of fractal scaling to quantify irregular aggregate morphologies. Finally, we correlate the macroscopic rheological properties of protein solutions with the occupied volume fraction and the aggregate structure. Overall, this work illustrates the power and limitations of colloidal approaches in the multiscale description of the aggregation of therapeutic proteins.

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On the role of salt type and concentration on the stability behavior of a monoclonal antibody solution

Cited by 81 publications

References 55 publications

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs

A multiscale view of therapeutic protein aggregation: A colloid science perspective

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