Autologous hinge-masked anti-TNFα antibody to mitigate immunogenicity, antigen sink effects, and anti-idiotypic antibody interference.
11 affiliations
- 1Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 2Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 3PrecisemAb Biotech Co., Ltd., Taipei, Taiwan.
- 4Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 5Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 6Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- 7School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 8School of Medicine, I-Shou University, Kaohsiung, Taiwan. [email protected].
- 9Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. [email protected].
- 10Department of Laboratory Medicine, Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. [email protected].
- 11Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. [email protected].
Abstract
Background
Monoclonal antibody (mAb) therapies are limited by factors affecting their pharmacokinetics (PK), such as anti-idiotypic antibodies (anti-ID Abs) and the antigen sink effect. To address this, we developed six pro-anti-TNFα Abs (pro-Infliximab) incorporating unique hinge regions ("Ab locks") from different immunoglobulin subtypes linked via protease-sensitive peptides. The steric shielding formed by the endogenous hinge's disulfide bonds provides a modular design that can be applied to various Ab drugs with minimal structural modification. Compared to other spatial hindrance strategies, this Ab lock approach is anticipated to offer a favorable immunogenicity profile.Results
Among the variants, The IgG1 hinge exhibited the most robust masking capability among the evaluated domains, resulting in a 128-fold reduction in Infliximab's antigen binding. IgG1 pro-Infliximab demonstrated low immunogenicity after repeated dosing and maintained stable PK in both naïve and immunized mice, retaining 74.2% serum levels one hour after TNFα challenge. It also reduced anti-ID Ab binding by 87.3-fold, while showing a trend toward decreasing Ab-mediated drug clearance in these treated mice.Conclusions
This IgG1 Ab lock strategy provides binding-level proof of concept for several pro-Abs, offering the potential to mitigate immunogenicity. It blocked systemic hTNFα in an acute target challenge model and reduced clearance to preserve pro-Infliximab PK, ultimately helping to enhance patient quality of life.
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BibTeX
@article{huang2026autologous,
title = {{Autologous hinge-masked anti-TNFα antibody to mitigate immunogenicity, antigen sink effects, and anti-idiotypic antibody interference.}},
author = {Bo-Cheng Huang and Yun-Chi Lu and Chih-Hung Chuang and Shih-Ting Hong and Kai-Wen Ho and Yi-An Cheng and Tzu-Yi Liao and En-Shuo Liu and Jun-Min Liao and Chiao-Yun Chen and Tian-Lu Cheng and I-Ju Chen and Wen-Wei Lin},
journal = {Journal of biological engineering},
year = {2026},
month = aug,
doi = {10.1186/s13036-026-00741-x},
url = {https://europepmc.org/article/MED/42958426},
note = {CC BY},
}
RIS
TY - JOUR
TI - Autologous hinge-masked anti-TNFα antibody to mitigate immunogenicity, antigen sink effects, and anti-idiotypic antibody interference.
AU - Bo-Cheng Huang
AU - Yun-Chi Lu
AU - Chih-Hung Chuang
AU - Shih-Ting Hong
AU - Kai-Wen Ho
AU - Yi-An Cheng
AU - Tzu-Yi Liao
AU - En-Shuo Liu
AU - Jun-Min Liao
AU - Chiao-Yun Chen
AU - Tian-Lu Cheng
AU - I-Ju Chen
AU - Wen-Wei Lin
PY - 2026
DA - 2026/08/01
JO - Journal of biological engineering
DO - 10.1186/s13036-026-00741-x
UR - https://europepmc.org/article/MED/42958426
AB - Background Monoclonal antibody (mAb) therapies are limited by factors affecting their pharmacokinetics (PK), such as anti-idiotypic antibodies (anti-ID Abs) and the antigen sink effect. To address this, we developed six pro-anti-TNFα Abs (pro-Infliximab) incorporating unique hinge regions ("Ab locks") from different immunoglobulin subtypes linked via protease-sensitive peptides. The steric shielding formed by the endogenous hinge's disulfide bonds provides a modular design that can be applied to various Ab drugs with minimal structural modification. Compared to other spatial hindrance strategies, this Ab lock approach is anticipated to offer a favorable immunogenicity profile.Results Among the variants, The IgG1 hinge exhibited the most robust masking capability among the evaluated domains, resulting in a 128-fold reduction in Infliximab's antigen binding. IgG1 pro-Infliximab demonstrated low immunogenicity after repeated dosing and maintained stable PK in both naïve and immunized mice, retaining 74.2% serum levels one hour after TNFα challenge. It also reduced anti-ID Ab binding by 87.3-fold, while showing a trend toward decreasing Ab-mediated drug clearance in these treated mice.Conclusions This IgG1 Ab lock strategy provides binding-level proof of concept for several pro-Abs, offering the potential to mitigate immunogenicity. It blocked systemic hTNFα in an acute target challenge model and reduced clearance to preserve pro-Infliximab PK, ultimately helping to enhance patient quality of life.
SN - 1754-1611
ER -