Life science
Medical & healthcare, Drug development

Development of cancer immunotherapy
using antigen glycan
Department of Chemistry, Graduate School of Science
Assistant Professor Yoshiyuki Manabe

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

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

Life science

Abstract
Glycans, the third life chain, are involved in many biologicalphenomena. Especially, glycans cover the cell surface as glycocalyx and provide the milieu for the first contact of the cell with theoutside environment, and therefore, they are closely related to selfand non-self-recognition processes, including immune responses.
On the other hand, the diversity and heterogeneity of glycan structures make their functional analysis and regulation difficult. Thus,
pharmaceutical applications of glycans have been limited. We aim
to elucidate and utilize the cell surface glycan functions by editing
the glycocalyx using synthesized glycans. We herein introduced
antigen glycan, whose antibodies abundantly exist in our body, tothe cell surface and successfully induced strong immune responses to the target cancer.

▍ Significance of the research and Future perspectiveGlycans cover the cell surface and interact with many biomolecules to regulate various biological phenomena. Therefore, thetechnology to edit the glycan structures of the cell surface provides
a new approach to control the event on bio-membranes, including
immune responses, intercellular communication, and signal transduction. In this study, we proposed a versatile method to regulate
the glycan functions of the cell surface by combining metabolic
glycan-labeling and caged strategy. We believe that this approachenables practical functional control of cell surface glycan to provide an innovative method for realizing glycodrugs.

▍ Background & Results

Glycan antigens such as α-gal (trisaccharide structure) and
α-rhamnose (α-Rha) are present in many organisms, such asbacteria, but humans do not have these glycans. Instead, humans
have a large number of natural antibodies against these glycans.
Therefore, these glycan antigens act as markers of non-self toinduce strong immune responses. In this study, we utilized theseantigen glycans for cancer immunotherapy. Namely, we introduced
glycan antigens on the cancer cell surface to induce immune
responses by recruiting their natural antibodies. After metabolic
incorporation of azido-sugar to the cell surface glycocalyx followedby α-Rha introduction by the click chemistry, immune response
was induced. To enhance the practicality of this method, we herein
employed caged strategy, in which tentatively protected α-Rha
was activated by photo-irradiation after the α-Rha introduction oncell surface. This strategy enhanced the efficacy of click chemistry by preventing the capture of α-Rha by their antibodies underpromiscuous conditions. Furthermore, this strategy enables theswitching of glycan functions by photo-irradiation. Consideringthat glycans function through the interactions with various biomolecules, spatiotemporal control of such interactions is essential for
exploiting glycan functions and was achieved using the cagingstrategy.

Figure 1 Functional analysis and regulation ofcell surface glycans by chemical approach

Figure 2 Immune induction through antibody recruiting strategy using caged glycan

P a t e n t
Tr e a t i s e

Manabe, Yoshiyuki; Fukase, Koichi et al. Practical antibody recruiting by metabolic labeling with caged glycans. Angew. Chem. Int. Ed. 2023, 62,e202303750. doi: 10.1002/anie.202303750
Manabe, Yoshiyuki; Fukase, Koichi et al. Development of α-gal antibody conjugates to increase immune response by recruiting natural antibodies.
Angew. Chem. Int. Ed. 2019, 58, 4526-4530. doi:10.1002/anie.201812914

URL
K e y w o r d glycan, antibody, immunity, photo-switching