Due to their excellent specificity, antibodies are among the most important molecular targeted drugs for various diseases. In this study, we developed α-gal antibody conjugates that dramatically increased cellular cytotoxicity by recruiting natural antibody through α-gal/anti-Gal antibody interaction .
α-Gal epitope (Galα1-3Galβ1-4GlcNAc-R) is expressed abundantly on glycolipids and glycoproteins in non-primate mammals, prosimians, and New World monkeys. Humans do not have α-gal due to inactivation of α-1,3-galactosyltransferase. Instead, they make large quantities of anti-Gal antibodies, which specifically interact with α-gal. Anti-Gal antibodies are the most abundant natural antibodies found in humans (1–2% of total serum IgG and 3–8% of total IgM). Consequently, α-gal antigen causes an acute immune response. α-Gal/anti-Gal antibodies interaction following xenotransplantation from pig to baboon induced hyperacute rejection of the transplanted tissues.
In this study, we applied the ADC (antibody-drug conjugate) concept to develop a novel α-gal-based tumor immunotherapy. Because α-gal antigen causes an extremely strong immune response, anti-tumor antibodies conjugated with α-gal was expected to have high potency against tumors.
After chemical synthesis of α-gal, we achieved concise chemical conjugation of antibodies with α-gal. The synthesized α-gal antibody conjugates efficiently provoked an immune response. The potency of α-gal antibody conjugates depended on the α-gal loading ratio. The larger the amount of α-gal was introduced, the higher the cytotoxicity was observed. Utilization of α-gal dendrimer allowed introduction of large amounts of α-gal epitope to the antibody without loss of affinity for the target cell. The method described here will enable re-development of antibodies to improve their potency.
- Sianturi J, Manabe Y, Li HS, Chiu LT, Chang TC, Tokunaga K, Kabayama K, Tanemura M, Takamatsu S, Miyoshi E, Hung SC, Fukase K. Development of α-Gal Antibody Conjugates for Increasing Immune Response by Recruiting Natural Antibodies. Angew Chem Int Ed Engl. 2019. doi: 10.1002/anie.201812914.