On September 9, the R & D team of Thoth Institutes (Nanjing) and Nanjing RegeneCore Biotech Co.,Ltd cooperated with the team of Professor Gaojie Song of East China Normal University to explore the structural basis for the action of bispecific nanobodies targeting IL-4Rα/IL-5. Some results were published in the famous academic periodical medcomm (Qiu, et al., Structural insight into interleukin-4Rα and interleukin-5 inhibition by nanobodies from a bispecific antibody,  09 September 2024）.This study showed that the screened nanobody Dab1 exhibited highly specific binding ability and signal blocking activity to human IL-4Rα.

Fig. Crystal structure of IL-4Rα in complex with dAb1 (left) and comparison with the IL-4–IL-4Rα (middle) or Dupilumab–IL-4Rα (right).

Cytokines such as IL-4Rα and IL-5 play important roles in human immune regulation and type II inflammation. Regenecore used own nanobody platform to screen and construct bispecific nanobodies targeting IL-4Rα and IL-5. The joint team solved the complex structure of IL-4Rα and its corresponding monoclonal antibody by combining structural biology methods, and the latter explained the molecular mechanism by which the antibody blocked the interaction between IL-4Rα and its ligand: the antibody mainly binds to the key loop on IL-4R α through its own hydrophobic pocket, which is also an important site for its binding ligand. At the same time, the team also used molecular modeling and mutant biochemical experiments to suggest the possible binding site and inhibition mechanism of the nanobody corresponding to IL-5.

This work was supported by the National Natural Science Foundation of China, the basic research program of Science and Technology Commission of Shanghai Municipality, and the thoth institutes for health project.

Original Article Link：https://doi.org/10.1002/mco2.700