Identification of Engineered IMGT Fc Variants in IMGT/mAb-DB Therapeutic Antibodies and Fusion proteins

Abstract

Monoclonal antibodies (mAbs) and fusion proteins for immune applications (FPIA) play a crucial role in treating autoimmune diseases and cancers by targeting cell-surface proteins and triggering multiple immune mechanisms. These functions are mediated by the fragment crystallizable (Fc) region of mAbs and fusion proteins, whose interaction with Fc gamma receptors (Fc{gamma}Rs) can be modulated through Fc amino acid (AA) engineering. To address this, we developed the IMGT/FcVariantsExplorer tool (https://www.imgt.org/fcvariantsexplorer/) to identify AA changes within the Fc region in mAb and fusion proteins sequences from IMGT/2Dstructure-DB, the AA sequence database of IMGT(R), the international ImMunoGeneTics information system(R). We used the IMGT(R) nomenclature of engineered Fc variants involved in antibody effector properties and formats, applying a standardized classification in five categories: Effector, Half-life, Physicochemical properties, Structure, and Hybrid. We analyzed sequences of 1,107 mAbs and fusion proteins, identifying 483 entries with Fc AA changes, resulting in 211 unique Fc variants in the dataset. We also used web scraping to retrieve associated biological data from literature. All data have been integrated into IMGT/mAb-DB, with links to sequences in IMGT/2Dstructure-DB, enabling users to query Fc variants by their Category or Effect. This curated dataset reveals key trends in antibody engineering.