A stealth-body Fc engineering platform enables complete effector silencing in antibody and ADC therapeutics

Abstract

Abstract

The development of next-generation antibody therapeutics requires Fc scaffolds that suppress unwanted effector functions while preserving core developability attributes. Existing effector-attenuated Fc backbones, however, retain residual interactions with Fcγ receptors (FcγRs) and C1q, highlighting a persistent design limitation in achieving complete effector silencing without compromising glycosylation, FcRn-mediated persistence, and manufacturability. This is particularly relevant for formats in which Fc effector function is undesirable, including immune-engaging antibodies, CD47 blockers, and antibody–drug conjugates (ADCs). Accordingly, a robust Fc engineering framework enabling complete and transferable effector silencing across antibody modalities is required. We developed Stealth-Body (SB) Fc variants, a fully effector-silenced Fc platform that abolishes Fc-mediated immune engagement while maintaining native-like glycosylation, pharmacokinetics, and manufacturability. Using a CHO cell display system with directed evolution guided by cross-species sequence features from goat IgG, we identified human glycosylated IgG1 variants (SB1, SB5, SB6) that abrogated binding to all human FcγRs and C1q, and to all murine and cynomolgus FcγRs. SB Fc retained pH-dependent FcRn binding, antigen recognition, thermostability, and expression, with in vivo persistence comparable to wild-type IgG1. Incorporation of SB Fc into trastuzumab, rituximab, and ADCs abolished ADCC, ADCP, and CDC, while integration into a CD47-targeting IgG–CD40L fusion protein mitigated hematologic toxicity without impairing immune activation. Collectively, SB Fc variants represent a generalizable, effector-null Fc scaffold that enables complete and transferable silencing of Fc-mediated immune functions while preserving key developability attributes. This platform expands the therapeutic window of antibody therapeutics through precise control of Fc activity across diverse modalities.