A stealth-body Fc engineering platform enables complete effector silencing in antibody and ADC therapeutics.
12 affiliations
- 1Department of Biomedical Sciences, Graduate School, Korea University, Seoul, 02841, Republic of Korea.
- 2BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, 02841, Republic of Korea.
- 3Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea.
- 4Department of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul, 08826, Republic of Korea.
- 5Manufacturing Science & Technology Team, Samsung Bioepis, Manufacturing Science Group2, Incheon, 21987, Republic of Korea.
- 6CrossPoint Therapeutics Inc., Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
- 7Department of Next Generation Applied Sciences, Sungshin Women's University, Seoul, 01133, Republic of Korea.
- 8Institute of Chemical Processes, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
- 9Department of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
- 10Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
- 11BioMAX, Seoul National University, Seoul, 08826, Republic of Korea. [email protected].
- 12Seoul National University Medical Research Center (SNUMRC), Seoul, 03080, Republic of Korea. [email protected].
Abstract
Background
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.Results
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.Conclusions
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.
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BibTeX
@article{kim2026stealthbody,
title = {{A stealth-body Fc engineering platform enables complete effector silencing in antibody and ADC therapeutics.}},
author = {Suyeon Kim and Migyeong Jo and Munsu Kyung and Woo Hyung Ko and Wonju Lee and Kihwan Chang and Pedro Lee and Sungkuk Cho and Seongin Seomun and Byoung Joon Ko and Tae-Erk Kim and Jungmin Choi and Sang Taek Jung},
journal = {Journal of biological engineering},
year = {2026},
month = jul,
doi = {10.1186/s13036-026-00735-9},
url = {https://europepmc.org/article/MED/42928316},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A stealth-body Fc engineering platform enables complete effector silencing in antibody and ADC therapeutics.
AU - Suyeon Kim
AU - Migyeong Jo
AU - Munsu Kyung
AU - Woo Hyung Ko
AU - Wonju Lee
AU - Kihwan Chang
AU - Pedro Lee
AU - Sungkuk Cho
AU - Seongin Seomun
AU - Byoung Joon Ko
AU - Tae-Erk Kim
AU - Jungmin Choi
AU - Sang Taek Jung
PY - 2026
DA - 2026/07/01
JO - Journal of biological engineering
DO - 10.1186/s13036-026-00735-9
UR - https://europepmc.org/article/MED/42928316
AB - Background 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.Results 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.Conclusions 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.
SN - 1754-1611
ER -