Hinge Region Cys-to-Ser Mutation Enables Homogeneous DAR6 Anti-c-Met Biparatopic ADCs with Tolerable O-Glycosylation

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ID: 323129
2026
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Abstract
Abstract Background Antibody–drug conjugates (ADCs) with homogeneous drug-to-antibody ratios (DARs) are increasingly favored for their improved physicochemical and pharmacokinetic properties; however, strategies to reliably generate homogeneous DAR6 ADCs remain limited. Methods In this study, we investigate hinge-region cysteine engineering as an approach to constrain conjugation stoichiometry, using a potent biparatopic anti–c-Met antibody as a model. Various biological and physicochemical assays were used for its characterization. Results We show that substitution of a hinge-region cysteine within a CPPC motif reduces the number of accessible conjugation sites, allowing reproducible generation of homogeneous DAR6 ADCs. During characterization of Ser- or Thr-substituted hinge variants, we observed additional mass species consistent with mucin-type O-linked glycosylation. Site-specific mass spectrometry analyses localized these modifications to a serine residue within hinge-region and identified the core structures of the O-glycans. Analysis of additional antibodies carrying analogous mutations demonstrated that hinge-associated O-glycosylation is not restricted to a single antibody scaffold. Conclusions These results demonstrate that hinge-region cysteine engineering can serve as a rational and adaptable approach for DAR6 ADC development while highlighting the need for case-by-case evaluation of associated post-translational modifications during antibody engineering.
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Authors Deyong Song, Zhenduo Shen, Xiaolin Zhu, Haifeng Zhao, Yingdi Wang, Junmei Zhang, Rui Li, Hongguang Xu, Zengjin Cheng, Xiaoju Ma, Haixia Lin, Changlin Dou, Min Xiao
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Journal Antibody Therapeutics
Year 2026
DOI
10.1093/abt/tbag040
URL
https://doi.org/10.1093/abt/tbag040
Keywords Keywords not found

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