Where disease pathogenesis meets protein formulation: renal deposition of immunoglobulin aggregates.
Aggregation is one of the important issues encountered during the development of immunoglobulin-based drugs. The aim of the current review is to discuss the causes and consequences of immunoglobulin aggregation as well as the relevance of immunoglobulin aggregation to disease pathogenesis. Extracellular deposition of immunoglobulins, either monoclonal light chains or intact polyclonal antibodies, induces renal failure in various nephropathies. The aggregates can present fibrillar or amorphous structures. In this review, factors known to influence protein aggregation, such as the primary structure of the protein, local environment and glycosylation are assessed, as well as the subsequent altered clearance, fibril formation and toxicity. The role of the protein local environment is emphasized. Even if the local environment causes only minor perturbations in the protein structure, these perturbations might be sufficient to trigger aggregate formation. This fact underlines the importance of choosing appropriate formulations for protein drugs. If the formulation provides a slightly destabilizing environment to the protein, the long-term stability of the drug may be compromised by aggregate formation.
Demeule
Barthélemy
B
School of Pharmaceutical Sciences, EPGL, University of Geneva, Switzerland.
Gurny
Robert
R
Arvinte
Tudor
T
D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism; D000818:Animals; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005922:Glomerulonephritis, IGA / Q000209:etiology / Q000378:metabolism; D006031:Glycosylation; D006362:Heavy Chain Disease / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary
D000682:Amyloid; D007136:Immunoglobulins