Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML

• Main Authors: Battula, V.L (Author), Bühring, H.-J (Author), El-Dana, F. (Author), Grimm, S. (Author), Jaggupilli, A. (Author), Konopleva, M. (Author), Ly, S. (Author), Tyagi, A. (Author), Yuan, B. (Author)
• Format: Article
• Language: English
• Published: Elsevier B.V. 2022
• Online Access: View Fulltext in Publisher
• ISBN: 00064971 (ISSN)
• DOI: 10.1182/blood.2021014671

We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop region of B7-H3, which is known to regulate the immunosuppressive function of B7-H3. Furthermore, treatment with ChT-1A5 in combination with human NK cells significantly prolonged survival in AML patient-derived xenograft (PDX) models. Our results suggest that the ChT-1A5 antibody can inhibit the immunosuppressive function of B7-H3 protein as well as induce ADCC in B7-H3+ AML. © 2022 American Society of Hematology