TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignancies

• DOI: 10.1172/jci.insight.97805
• Publication Date: 2018-02-21T16:00:58Z
• Authors: Mahiuddin Ahmed; Andres Lopez-Alba...; Dmitry Pankov; Brian H. Santich; Hong Liu; Su Yan; Jingyi Xiang; Pei Wang; Aisha N. Hasan; Annamalai Selvakumar; Richard J. O’Reilly; Cheng Liu; Nai-Kong V. Cheung
• Keywords: clone (Java method)

EBV infection is associated with a number of malignancies clinical unmet need, including Hodgkin lymphoma, nasopharyngeal carcinoma, gastric cancer, and posttransplant lymphoproliferative disease (PTLD), all which express the protein latent membrane 2A (LMP2A), an antigen that difficult to target by conventional antibody approaches. To overcome this, we utilized phage display technology structure-guided selection strategy generate human T cell receptor-like (TCR-like) monoclonal antibodies exquisite specificity for LMP2A-derived nonamer peptide, C426LGGLLTMV434 (CLG), as presented on HLA-A*02:01. Our lead construct, clone 38, closely mimics native binding mode TCR, recognizing residues at position P3-P8 CLG peptide. enhance antitumor potency, constructed dimeric engaging bispecific (DiBsAb) 38 affinity-matured version 38-2. Both DiBsAb showed potent properties in vitro immunodeficient mice implanted transformed B lymphoblastoid lines effectors. Clone stronger safety profile compared its variant, no activity against EBV- tumor panel normal tissues, was less cross-reactive HLA-A*02:01 cells pulsed CLG-like peptides predicted from proteomic analysis. also shown recognize peptide other HLA-A*02 suballeles, HLA-A*02:02, HLA-A*02:04, HLA-A*02:06, allowing potential use additional populations. candidate treat one strongest profiles documented TCR-like mAbs.