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

Authors: Ahmed, M.; Lopez-Albaitero, A.; Pankov, D.; Santich, B. H.; Liu, H.; Yan, S.; Xiang, J.; Wang, P.; Hasan, A. N.; Selvakumar, A.; O'Reilly, R. J.; Liu, C.; Cheung, N. K. V.
Article Title: TCR-mimic bispecific antibodies targeting LMP2A show potent activity against EBV malignancies
Abstract: EBV infection is associated with a number of malignancies of clinical unmet need, including Hodgkin lymphoma, nasopharyngeal carcinoma, gastric cancer, and posttransplant lymphoproliferative disease (PTLD), all of which express the EBV protein latent membrane protein 2A (LMP2A), an antigen that is difficult to target by conventional antibody approaches. To overcome this, we utilized phage display technology and a structure-guided selection strategy to generate human T cell receptor-like (TCR-like) monoclonal antibodies with exquisite specificity for the LMP2A-derived nonamer peptide, C-426 LGGLITMV(434) (CLG), as presented on HLA-A*02:01. Our lead construct, clone 38, closely mimics the native binding mode of a TCR , recognizing residues at position P3-P8 of the CLG peptide. To enhance antitumor potency, we constructed dimeric T cell engaging bispecific antibodies (DiBsAb) of clone 38 and an affinity-matured version clone 38-2. Both DiBsAb showed potent antitumor properties in vitro and in immunodeficient mice implanted with EBV transformed B lymphoblastoid cell lines and human T cell effectors. Clone 38 DiBsAb showed a stronger safety profile compared with its affinity-matured variant, with no activity against EBV- tumor cell lines and a panel of normal tissues, and was less cross-reactive against HLA-A*02:01 cells pulsed with a panel of CLG-like peptides predicted from a proteomic analysis. Clone 38 was also shown to recognize the CLG peptide on other HLA-A*02 suballeles, including HLA-A*02:02, HLA-A*02:04, and HLA-A*02:06, allowing for its potential use in additional populations. Clone 38 DiBsAb is a lead candidate to treat EBV malignancies with one of the strongest safety profiles documented for TCR-like mAbs.
Keywords: peptide; recognition; phage display; epitopes; specificity; histocompatibility complex; epstein-barr-virus; tumor-associated antigen; t-cell-receptor; human recombinant antibodies; major; restricted
Journal Title: JCI Insight
Volume: 3
Issue: 4
ISSN: 2379-3708
Publisher: Amer Soc Clinical Investigation Inc  
Date Published: 2018-02-22
Start Page: e97805
Language: English
ACCESSION: WOS:000426013400013
DOI: 10.1172/jci.insight.97805
PUBMED: 29467338
Notes: Article -- Source: Wos
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MSK Authors
  1. Nai-Kong Cheung
    439 Cheung
  2. Mahiuddin Ahmed
    12 Ahmed
  3. Dmitry D. Pankov
    18 Pankov
  4. Aisha Nasreen Hasan
    47 Hasan
  5. Richard O'Reilly
    468 O'Reilly