%0 Journal Article
%A Abu Ahmad, Muhammad
%A Radinsky, Olga
%A Kaufman, Bar
%A Waidha, Kamran
%A Gharra, Eman
%A Dim, Sharon
%A Manikandan, Dinesh Babu
%A Ofir, Noa
%A Jäger, Dirk
%A Meyer, Marten
%A Elkabets, Moshe
%A Campbell, Kerry S
%A Zektser, Miri
%A Gazit, Roi
%A Rouvio, Ory
%A Momburg, Frank
%A Porgador, Angel
%T HLA-E[pHLA-G] Complex Specific Monoclonal Antibody Enhancing NK Activity in Multiple Myeloma.
%J Blood advances
%V nn
%@ 2473-9529
%C Washington, DC
%I American Society of Hematology
%M DKFZ-2025-01533
%P nn
%D 2025
%Z epub
%X HLA-E presenting the HLA-G leader peptide VMAPRTLFL (HLA-E[pHLA-G]) on tumor cells plays a crucial role in suppressing natural killer(NK) and cytotoxic CD8+ T cells through NKG2A interaction. While blocking HLA-E:NKG2A is a promising immune checkpoint(IC) approach in cancer therapy, toxicity remains a major clinical concern. We developed a novel immune checkpoint inhibitor(ICI) that selectively prevents HLA-E:NKG2A interaction, a monoclonal antibody(mAb) that selectively targets the HLA-E[pHLA-G] complex, distinguishing cancerous from non-cancerous cells. In clinical bone marrow samples from multiple myeloma(MM) patients, 4D7 specifically recognized tumor-associated HLA-E-peptide complexes. Using NK cells from healthy donors, 4D7 effectively blocked the HLA-E:NKG2A interaction and enhanced NKG2A-positive NK cell activity in autologous MM cell co-cultures. Importantly, 4D7 did not inhibit NKG2C-positive NK cells, preserving their activity. Even though NKG2C also interacts with HLA-E. In MM-bearing mice treated with human NK cells, 4D7 significantly reduced tumor growth. This targeted approach activates NK cells only against tumor cells presenting HLA-E-peptide complexes, potentially minimizing toxicity compared to current NKG2A inhibitors. The development of 4D7 highlights a promising advancement in immunotherapy for hematological malignancies, offering improved outcomes for MM patients and a foundation for broader application across cancer types.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40706037
%R 10.1182/bloodadvances.2025016276
%U https://inrepo02.dkfz.de/record/303114