Dr. Koichi Fukase has been engaged in elucidating the function of complex glycans in the immune system based on molecular structures. He has been involved in developing efficient glycan synthesis methods and the chemical synthesis of various carbohydrates, contributing to the determination of active structures in innate immunity. Many natural constitute complex systems with multiple active structures within the molecule, potentially giving rise to emergent higher-order functions through synergistic interactions. Dr. Fukase has also succeeded in creating immunomodulatory complex glycans through an approach based on conjugation reactions of active fragments. Below are some of his main achievements:

1. Development of innate immunity-regulating molecules based on bacterial-host interactions and their application to novel adjuvants
Lipopolysaccharides (LPS) and their active center lipid A from Gram-negative bacteria have a potent immune-enhancing effect, attracting attention as adjuvants to enhance vaccine efficacy. However, they have been also known as endotoxins; they possess toxicity, including high fever, septic shock, multiple organ failure, coagulation abnormalities, lethal toxicity due to the robust inflammatory effects. Dr. Fukase aimed to develop safe and effective adjuvants by searching for lipid A molecules from symbiotic and parasitic bacteria that co-evolved with the host, with the expectation of moderately activating innate immunity while exhibiting low toxicity. Parasitic bacteria such as Helicobacter pylori and Porphyromonas gingivalis produce distinctive lipid A molecules with a monophosphoryl structure. Dr. Fukase succeeded in synthesizing the lipid A molecules and the LPS partial structures containing lipid A and the acidic sugar Kdo, discovering that they do not induce acute inflammation associated with bactericidal action but selectively activate chronic inflammation signals. He determined the structures of lipooligosaccharides (LOS) and lipid A from Alcaligenes faecalis, which cohabitates in Peyer's patches of intestinal mucosa, and succeeded in efficient synthesis of lipid A. A. faecalis lipid A has been shown to be an excellent adjuvant enhancing vaccine efficacy, as it effectively activates both mucosal and systemic immunity while exhibiting low inflammatory activity. It is currently under consideration for practical application.

2. Exploration of efficient synthesis for N-glycans
N-Linked glycoprotein glycans (N-glycans) have diverse structures and play important roles in immune regulation via lectin-glycan interactions. Dr. Fukase proposed a diacetyl strategy as a new synthetic strategy for N-glycans and other glycans containing the amide group (NHAc). He found that protected glycan intermediates containing NHAc form intermolecular hydrogen bonds in organic solvents, significantly reducing glycosylation reactivity. By protecting NHAc as an imide (NAc₂), he developed a method to significantly improve the reactivity of glycosylation reactions. Utilizing this method named the diacetyl strategy, he succeeded in the chemical synthesis of various N-glycans including fully sialylated tetra-antennary N-glycans.

3. Elucidation of the molecular basis for the immunomodulatory function of N-glycans
Core fucose is a major chemical modification of N-glycans and is involved in immunomodulation such as inhibition of antibody-dependent cellular cytotoxicity (ADCC) of antibody drugs. However, endogenous molecules that recognize core fucose in mammals were undiscovered. Dr. Fukase found that dectin-1, a β-glucan recognizing lectin, recognizes the core fucosylated IgG antibodies. Dr. Fukase discovered that in Dectin-1's recognition of IgG, the core fucosylated N-glycans alone do not interact with Dectin-1; instead, Dectin-1 simultaneously recognizes the core fucosylated N-glycans and the aromatic amino acids adjacent to the glycosylation site. He named this interaction heterovalent interaction. Meanwhile, he demonstrated that Siglec-2 interacts with two sialic acids on one bi-antennary N-glycan and showed that on the cell surface, the aggregation of Siglec-2 is promoted through interactions of Siglec-2 and N-glycans on Siglec-2. These results indicate that N-glycans and their conjugates function emergently based on multivalent as well as heterovalent recognitions.

4. Synthesis of artificial glycoconjugates for developing novel cancer immunotherapies
Many animals have the antigenic glycan termed α-gal, but humans do not. However, humans possess a large amount of anti-Gal antibodies as natural antibodies against this glycan, causing intense immune reactions with α-gal. Dr. Fukase successfully enhanced complement-dependent cytotoxicity (CDC) by recruiting anti-Gal antibodies to cancer cells by conjugation of α-gal with antitumor antibodies (anti-CD20 antibody and its half- antibody). A problem with using natural antibodies is that the antigen-antibody reaction occurs immediately after administering the glycan antigens. Therefore, he developed a method to introduce caged glycan antigens into cancer cells, releasing free glycans upon light irradiation, and then inducing an immune response.

5. Synthesis and functional evaluation of self-adjuvanting vaccines
Self-adjuvanting vaccines, which bind antigens and adjuvants, are noted as vaccines that effectively evoke antigen-specific immune responses with less inflammatory responses. However, those using tumor-associated carbohydrate antigens (TACA) were unexplored. Dr. Fukase developed a three-component conjugated vaccine, consisting of triSTn, a trimer of the TACA sialylTn (STn), the TLR2 adjuvant Pam3CSK4, and a T-cell epitope. He demonstrated that this vaccine strongly induces antibodies against triSTn and that the produced antibodies can efficiently recognize cancer cells. He showed that conjugation of the three components is essential for the antibody production. This conjugation-based method is also effective for peptide antigens derived from the cancer antigen Her2, such as the CH401 peptide antigen, allowing for universal application.

6. Research on targeted alpha therapy
Targeted alpha therapy (TAT) shows a potent cancer cell killing effect due to the high energy of α-particles and has characteristics such as minimal invasion to surrounding organs due to short flight range, and side effects can be kept low using astatine-211 (²¹¹At) with a half-life of 7.2 hours. Since 2015, Dr. Fukase has led TAT research at Osaka University, developing various drug candidates labeled with ²¹¹At produced in accelerators, including TAT drugs using fibroblast activation protein inhibitors (FAPI), and demonstrating their potent anti-cancer activity. TAT has been found to activate innate and antitumor immunity, and the development of effective cancer treatment methods in combination with the above immunotherapies is expected.
As described, Dr. Fukase has studied on the synthesis and functional study of complex glycans, contributing to their functional elucidation and successful higher-order functionalization through conjugation. These achievements have impacted not only chemistry but also related fields such as biology and medicine. Therefore, his achievements are recognized as worthy of the Chemical Society of Japan Award.