Precision Fc remodeling via glycosylation-competent CHO display enables ultra-selective FcγRIIIa targeting and enhanced antitumor activity

BACKGROUND: Improving tumor cell clearance by therapeutic antibodies remains a translational bottleneck because wild-type IgG1 Fc typically elicits suboptimal NK cell–mediated antibody-dependent cellular cytotoxicity (ADCC), necessitating Fc engineering to enhance activating FcγR engagement while preserving antigen specificity and manufacturability. FcγRIIIa (CD16A) is the principal activating receptor on NK cells, and its clinical relevance is underscored by the FCGR3A-158V/F polymorphism, which modulates IgG1 Fc affinity and therapeutic response. Because FcγRIIIa engagement critically depends on Fc glycosylation, microbial display platforms lacking mammalian glycan processing are limited in capturing Fc–FcγRIIIa energetics and selectivity. RESULTS: We developed a glycosylation-integrated Fc engineering platform using CHO surface display to screen glycosylated Fc libraries in a post-tra…