Development of alpha-gal conjugated anti-cancer antibodies

Session: 
S1.3 Glycolipid immunology
Code: 
OL1.3.3
Location (hall): 
Galactose
Start/end time: 
Monday, July 1, 2019 - 12:15 to 12:30
Koichi
Fukase

Koichi Fukase1, Julinton Sianturi1, Yoshiyuki Manabe1, Hao-Sheng Li1, Li-Ting Chiu2, Tsung-Che Chang1, Kento Tokunaga1, Kazuya Kabayama1, Masahiro Tanemura3, Shinji Takamatsu1, Eiji Miyoshi1, Shang-Cheng Hung2

1Osaka University, Toyonaka, Japan, 2Academia Sinica, Taipei, Taiwan, 3Osaka Police Hospital, Osaka, Japan

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 [1]. 

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.

Strategy for tumor immunotherapy using α-gal antibody conjugate.

References: 
  1. 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.

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