HLA-E[pHLA-G] Complex Specific Monoclonal Antibody Enhancing NK Activity in Multiple Myeloma Open Access

• A novel antibody selectively blocks the HLA-E[pHLA-G]:NKG2A IC, enhancing NK cell attack on multiple myeloma while sparing healthy cells.

• This targeted approach reduces tumor growth in vivo and may minimize toxicity compared to current NKG2A inhibitors.

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.