ArticleBioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy2025
Interrogation of Structure-Activity Relationships in Charge Variants of Therapeutic IgG2s Enabled by Free-Flow Isoelectric Focusing Fractionation.
Article in BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundRecombinant immunoglobulin G2 (IgG2) antibodies are effective neutralization agents or antagonists with high medical value because of their high specificity, long half-life, and absent effector functions. During biopharmaceutical process development, charge heterogeneity and bioactivity alternation related to charge variation should be investigated to understand the structure-activity relationship (SAR) in therapeutic antibodies. Isoelectric focusing can provide fine resolution for the charge heterogeneity profiling of IgG2, while ion exchange chromatography cannot achieve effective separation of IgG2 charge variants. In-depth investigation of charge heterogeneity requires a fractionation tool to enrich and isolate acidic and basic variants.
objectivesThis study aims to investigate the structural origins and functional implications of charge heterogeneity in two therapeutic IgG2 antibodies, including an anti-receptor activator of nuclear factor κ-B ligand (RANKL) biosimilar of denosumab and an innovative anti-CD73 IgG2 (H-mab), using free-flow isoelectric focusing (FF-IEF).
methodsCharge variants of denosumab and H-mab were fractionated using FF-IEF, followed by characterization of isolated IgG2 charge variants to establish the SAR between charge-related antibody modifications and bioactivities. The investigation incorporated in silico 3D modeling of the FcRn-IgG2 Fc complex and the CD73-Fab complex to facilitate the SAR interrogation of these two IgG2s.
resultsThe acidic charge variants of denosumab were driven primarily by N-glycan sialylation and deamidation in the Fc region, showing negligible effects on biological functions except for a reproducible reduction in FcRn binding affinity. In contrast, the basic charge variants of H-mab were associated with D
conclusionsThis study underscores the irreplaceable role of FF-IEF in both biosimilar and innovative therapeutic pipelines, highlighting the importance of monitoring charge heterogeneity and understanding SAR in therapeutic IgG2 antibodies.
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