Stability of monoclonal antibodies (mAbs)

Physicochemical Stability of Monoclonal Antibodies: A Review

“…Protein degradation can result from many different instability mechanisms that can be divided into chemical and physical instabilities. Those instabilities are closely intertwined, as chemical reactions can lead to physical instability 29 and physical instability may give access to chemically susceptible residues or close the gap between residues that may interact, 28 even if it is hard to know what was the original cause of instability. For example, Luo et al 30 showed the presence of several chemical modifications in aggregates; however, they did not conclude about wither those modifications existed or not before aggregation.…”

“…It may happen in presence of oxidants (such as peroxides, light, or metals) or without, then referred to as auto-oxidation. 28 Some residues are particularly susceptible to oxidation, including methionine, histidine, and cysteine residues. 28,31 Disulfide bond formation is one of the consequences of cysteine oxidation that occurs between 2 oxidized free residues, with a thiolate anion intermediate.…”

“…28 Some residues are particularly susceptible to oxidation, including methionine, histidine, and cysteine residues. 28,31 Disulfide bond formation is one of the consequences of cysteine oxidation that occurs between 2 oxidized free residues, with a thiolate anion intermediate. 24 The formation of those bridges may be intramolecular or intermolecular, and is enhanced in basic environment.…”

“…24 The formation of those bridges may be intramolecular or intermolecular, and is enhanced in basic environment. 28 Another major chemical degradation process of proteins is deamidation, affecting mostly asparagine and, in a lesser extent, glutamine residues. It is an acid-base reaction, facilitated by the presence of specific nearby residues that may act as proton donors (threonine or serine for example), which results in the formation of a cyclic imide intermediate that can cause a distortion in the polypeptidic structure.…”

“…Clinical consequences of such events are still under investigation, especially with regard to the immunogenicity potential, 18 and available data are not always reassuring, as several publications have shown an enhanced immune response due to aggregates, even though the relationship is not fully understood and seems dependent on the degradation pathway. [19][20][21][22] Despite there being many excellent reviews on the overall subject of protein stability, [23][24][25][26][27][28] the objective of this work is to propose an up-to-date review about mAb stability and a compilation of data from different published stability studies of mAbs, either in their reconstituted form, or in diluted ready to administer solutions, to give readers a comparative overview of postmarketing stability studies and to point out their potential lack of compliance to recommendations for protein stability studies through a gradation proposal. For a complete comprehension, we will first briefly describe the different instability mechanisms mAbs are subjected to and the parameters and conditions affecting their stability, before going into a description of the different analytical methods used for appropriate physicochemical stability studies, and eventually present the compilation itself.…”