TY  - JOUR
AU  - Abu Ahmad, Muhammad
AU  - Radinsky, Olga
AU  - Kaufman, Bar
AU  - Waidha, Kamran
AU  - Gharra, Eman
AU  - Dim, Sharon
AU  - Manikandan, Dinesh Babu
AU  - Ofir, Noa
AU  - Jäger, Dirk
AU  - Meyer, Marten
AU  - Elkabets, Moshe
AU  - Campbell, Kerry S
AU  - Zektser, Miri
AU  - Gazit, Roi
AU  - Rouvio, Ory
AU  - Momburg, Frank
AU  - Porgador, Angel
TI  - HLA-E[pHLA-G] Complex Specific Monoclonal Antibody Enhancing NK Activity in Multiple Myeloma.
JO  - Blood advances
VL  - nn
SN  - 2473-9529
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2025-01533
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40706037
DO  - DOI:10.1182/bloodadvances.2025016276
UR  - https://inrepo02.dkfz.de/record/303114
ER  -