Life science
Medical & healthcare, Drug development

Control of antibody dynamics
and activity by glycan modification

Life science

Department of Chemistry, Graduate School of ScienceAssistant Professor Yoshiyuki Manabe		

https://researchmap.jp/researchmap_manabe?lang=en

Associate Professor Kazuya Kabayama		

https://researchmap.jp/KK007398?lang=en

Professor Koichi Fukase 				https://researchmap.jp/read0076573?lang=en

Abstract
Glycans, the third life chain, are involved in many biologicalphenomena. On the other hand, the diversity and heterogeneityof glycan structures make their functional analysis and regulationdifficult. Thus, pharmaceutical applications of glycans have beenlimited. We aim to elucidate and utilize the cell surface glycanfunction through chemical approach. Considering that glycans areconjugated with proteins or lipids in nature, we are investigating
glycan functions by conjugating the synthesized glycans with otherbiomolecules, such as proteins. In this study, we conjugated theglycan to the antibody drug and successfully improve their immune
induction activity by suppressing their internalization into cells. This
study proposed a novel approach to exploit glycan functions forcontrolling protein activity.

tures. In this study, we propose a versatile method to control protein
dynamics and activity by chemical conjugation of glycans, which isexpected to be applied to upgrade the functions of various proteindrugs.

▍ Background & Results
Antibody drugs are one of the most important molecular-targeteddrugs with high specificity. Conversely, their insufficient efficacy
has been a critical issue in many cases. Thus, new trends in molecular-targeted drug development are enhancing the potency ofantibody drugs. Here, we aimed to enhance antibody potency bycontrolling its dynamics on the target cell surface by conjugatingglycan. Antibody activity is closely related to its dynamics. For
example, when antibodies are taken up into the target cell by endocytosis, they cannot induce adequate immune responses. On
the other hand, glycans cover the cell surface as a glycocalyx
and interact with various molecules on the membrane, playing animportant role in regulating the dynamics of biomolecules on thecell surface, including internalization by endocytosis. Therefore, we
utilized the glycan-lectin interaction to regulate antibody dynamics
and activity.
In this study, an anti-HER2 antibody, an anti-breast cancer antibody, was conjugated with galactose-containing N-glycan, andits internalization was suppressed by interaction with galectin-3,
leading to the enhancement of immune induction activity. Although
there are many reports on the modification of the inherent N-glycan
structure of the Asn297 of antibodies, the present approach, inwhich the glycan was additionally attached to the antibody, proposes a novel approach to modulate antibody activity. To the best of
our knowledge, this is the first demonstration of the active control ofantibody dynamics by glycan conjugation. Since this method uses
endogenous N-glycan and employs the glycan-lectin interaction inhuman bodies, no or few adverse effects are expected. Therefore,
this approach might provide an alternative strategy for re-developing therapeutic antibodies and their candidates to improve potency.

Figure 1 Elucidation and regulation of glycan functions by chemical approach

Figure 2 Control of antibody dynamics and potency by conjugating glycan▍ Significance of the research and Future perspective
Glycans are the most abundant post-translational modification,and more than 60% of proteins are modified with glycans. The
attached glycans regulate protein functions based on their struc-P a t e n t
Tr e a t i s e

Manabe, Yoshiyuki; Kabayama, Kazuya; Fukase, Koichi et al. Improvement of antibody activity by controlling its dynamics using the glycan-lectininteraction. Angew. Chem. Int. Ed. 2023, 62, e202304779. doi: 10.1002/anie.202304779

URL
K e y w o r d glycan, antibody, immunity, lectin