Function-structure approach reveals novel insights on the interplay of Immunoglobulin G 1 proteoforms and Fc gamma receptor IIa allotypes
نویسندگان
چکیده
Human Fc gamma receptor IIa (FcγRIIa) or CD32a has two major allotypes with a single amino acid difference at position 131 (histidine arginine). Differences in FcγRIIa are known to impact immunological responses such as the clinical outcome of therapeutic monoclonal antibodies (mAbs). is involved antibody-dependent cellular phagocytosis (ADCP), which an important contributor mechanism-of-action mAbs by driving phagocytic clearance cancer cells. Hence, understanding individual mAb proteoforms on binding FcγRIIa, and its different allotypes, crucial for defining meaningful critical quality attributes (CQAs). Here, we report function-structure based approach guided novel affinity chromatography-mass spectrometry (AC-MS) assays assess IgG1 proteoforms. This allowed unravel allotype-specific differences binding. AC-MS confirmed refined structure-function relationships glycoform interactions. For example, positive afucosylation was higher than galactosylation Arg compared His. Moreover, observed allotype-opposing proteoform integrity-dependent response stress-induced comprising asparagine 325 deamidation. The FcγRIIa-allotype dependent resolved were line functional ADCP-surrogate bioassay models. molecular basis allotype specificity selectivity upon deamidation elucidated using dynamics. attributed contributions inter-molecular salt bridge between contribution intra-molecular hydrophobic pocket IgG1. Our work highlights unprecedented structural resolution approaches along predictive biological significance within relevant cell-based methods. makes invaluable tool streamline CQA assessment mAbs.
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ژورنال
عنوان ژورنال: Frontiers in Immunology
سال: 2023
ISSN: ['1664-3224']
DOI: https://doi.org/10.3389/fimmu.2023.1260446