Structural modeling and biochemical studies reveal insights into the molecular basis of the recognition of β-2-microglobulin by antibody BBM.1

✍ Scribed by Jiamu Du; Hui Yang; Baozhen Peng; Jianping Ding

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 410 KB
• Volume: 22
• Category: Article
• ISSN: 0952-3499
• DOI: 10.1002/jmr.964

✦ Synopsis

Abstract

Human β‐2‐microglobulin (__β__2m) is the light chain of human leucocyte antigen‐I (HLA‐I). It can disassociate from HLA‐I and accumulate to cause serious dialysis‐related amyloidosis (DRA) in long‐term hemodialysis patients. Monoclonal antibody (mAb) BBM.1 can recognize both free‐form and HLA‐I associated __β__2m. It can be used for specific elimination of __β__2m from serum and can induce apoptosis of several types of tumor cells, and thus has great therapeutic potential. In this study, we constructed structural models of the BBM.1 Fv (fragment of the variable domain) and the BBM.1 Fv‐__β__2m complex, followed by biochemical evaluation. Analysis of the optimal complex model reveals that the previously identified immunodominant residues Glu^44^ and Arg^45^ of __β__2m have direct interactions with BBM.1, while Asp^38^ exerts its function mainly via stabilization of Arg^45^. In addition, Arg^81^ of __β__2m is a newly identified immunodominant residue to have direct interaction with BBM.1. Further modeling study shows no steric conflict between the antibody and the HLA‐I heavy chain. These results provide insights into the molecular basis of the recognition of __β__2m by BBM.1 and explain why BBM.1 can bind both free‐form and HLA‐1 associated __β__2m. This information could be exploited in the engineering and improvement of BBM.1 and the development of other __β__2m‐targeting mAbs for therapeutic purposes. Copyright © 2009 John Wiley & Sons, Ltd.