When Does Fc Add Value? Context-Dependent Fc Biology and Engineering of Therapeutic Broadly Neutralizing Antibodies for HIV-1

Broadly neutralizing antibodies (bNAbs) have emerged as a promising therapeutic strategy for HIV-1 prevention and treatment, but their efficacy extends far beyond their direct antiviral capacity. In addition to traditional Fab-mediated neutralization, the Fc domain engages cellular and molecular pathways to complement antiviral immunity. The Fc domain achieves this through orchestrated interactions with Fc gamma receptors (FcγR) and effector cells. In turn, these events are modulated according to antibody structure, glycosylation patterns, and the local immune microenvironment. Early work established that N297 glycosylation fundamentally governs Fc function, with concurrent studies revealing how effector cell activation drives antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These discoveries prompted systematic approaches to Fc engineering, allowing researchers to selectively enhance or diminish effector functions to match distinct clinical goals. More recent evidence shows that Fc optimization cannot ignore epitope geometry, Fc receptor availability, and effector cell composition, which vary across anatomical sites and among individuals with different comorbidities. Together, these insights have enabled the design of Fc-engineered antibodies tailored to specific therapeutic needs, from long-acting prevention to combination treatment and emerging cure strategies. Yet significant gaps remain: the tissue-level mechanisms underlying viral escape, the clinical predictivity of in vitro assays, and the integrated approaches needed to overcome anatomical, immunological, and virological barriers that continue to limit efficacy. Addressing these questions requires validation studies that bridge cellular assays and clinical outcomes.