Distinct binding mode of BAFF antagonist antibodies belimumab and tabalumab, analyzed by computer simulation.

B cell-activating factor (BAFF) can bind with specific receptors to activate signalling pathways associated with the B cell activation. Belimumab and tabalumab are anti-BAFF (B cell depleting) monoclonal antibodies, with therapeutic efficacy demonstrated for the treatment of autoimmune disorders, while belimumab was approved by FDA in 2011 as a targeted therapy for systemic lupus erythematosus (SLE) and exhibited better clinical outcome than tabalumab. In this investigation, the combination modes of BAFF-belimumab and BAFF-tabalumab complexes were simulated in silico to better understand the reason for the comparative inhibitory difference between belimumab and tabalumab. The structures of belimumab and tabalumab were constructed through homology modelling. The combination mode of BAFF-belimumab complex was analyzed by molecular dynamics simulation, while that of BAFF-tabalumab complex was analyzed by protein-protein docking following the molecular dynamics simulation. Both belimumab and tabalumab were bound with BAFF at the same hydrophobic center to which the natural receptors of BAFF bind as well. Belimumab heavy chain components I51, F54, K58, D100, D101, L102, L103, and P105 and R27, Y30, K49, and S65 of belimumab light chain contribute to the BAFF-belimumab interaction mainly via hydrogen bonds, salt bridges, and hydrophobic interactions. More importantly, belimumab could bind to L83 of BAFF and produce steric hindrance with the adjacent BAFF trimers, while tabalumab could not. Therefore, our results indicated that belimumab has a better clinical outcome compared with tabalumab mainly because belimumab could bind to L83 of BAFF and interfere the formation of a BAFF 60-mer, besides mediating inhibition of the interaction of BAFF with its receptors.