抗 TRBC1 抗体结合模式的计算发现及 TRBC1 关键氨基酸预测

Peripheral T-cell lymphoma (PTCL) is a type of non-Hodgkin lymphoma that progresses aggressively with poor survival rate. CAR T cell targeting T-cell receptor -chain constant domains 1 (TRBC1) of malignant T cells has been developed recently by using JOVI. 1 monoclonal antibody as a template.

However, the mode of JOVI. 1 binding is still unknown. This study aimed to investigate the molecular interaction between JOVI. 1 antibody and TRBC1 by using computational methods and molecular docking.

Therefore, the TRBC protein crystal structures (TRBC1 and TRBC2) as well as the sequences of JOVI. 1 CDR were chosen as the starting materials. TRBC1 and TRBC2 epitopes were predicted, and molecular dynamic (MD) simulation was used to visualize the protein dynamic behavior. The structure of JOVI. 1 antibody was also generated before the binding mode was predicted using molecular docking with an antibody mode. Epitope prediction suggested that the N3K4 region of TRBC1 may be a key to distinguish TRBC1 from TCBC2.

MD simulation showed the major different surface conformation in this area between two TRBCs. The JOVI. 1-TRBC1 structures with three binding modes demonstrated JOVI. 1 interacted TRBC1 at N3K4 residues, with the predicted dissociation constant (K d ) ranging from 1. 5 10 8 to 1. 1 10 10 M. The analysis demonstrated JOVI. 1 needed D1 residues of TRBC1 for the interaction formation to N3K4 in all binding modes.

In conclusion, we proposed the three binding modes of the JOVI. 1 antibody to TRBC1 with the new key residue (D1) necessary for N3K4 interaction. This data was useful for JOVI. 1 redesign to improve the PTCL-targeting CAR T cell.