Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers

• DOI: 10.1136/jitc-2023-008145
• Publication Date: 2024-01-24T18:40:28Z
• Authors: Jianfei Qian; Qiang Wang; Liuling Xiao; Wei Xiong; Miao Xian; Pan Su; Maojie Yang; Chuanchao Zhang; Yabo Li; Ling Zhong; Siddhartha Ganguly; Youli Zu; Qing Yi
• Keywords: DKK1

Targeted immunotherapy with monoclonal antibodies (mAbs) is an effective and safe method for the treatment of malignancies. Development mAbs improved cytotoxicity, targeting new known tumor-associated antigens, therefore continues to be active research area. We reported that Dickkopf-1 (DKK1) a good target human cancers based on its wide expression in different but not normal tissues. As DKK1 secreted protein, binding directly have limited effects cancer cells vivo. The specificity antibody-binding capacity DKK1-A2 were determined using indirect ELISA, confocal imaging, QIFIKIT cell surface assays. affinity was plasmon resonance biosensor. A flow cytometry-based death performed detect tumor apoptosis. Antibody-dependent cellular cytotoxicity (ADCC) complement-dependent (CDC) assays used evaluate ability mediate ADCC CDC activities against vitro. Flow cytometry data collected FACSymphony A3 analyzer analyzed FlowJo V.10.1 software. Human xenograft mouse models determine vivo therapeutic efficacy potential safety toxicity mAbs. In situ TUNEL assay apoptosis tumors organs. generated novel recognize P20 peptide presented by HLA-A*0201 (HLA-A2) molecules (DKK1-A2 complexes) are naturally expressed HLA-A2+DKK1+ cells. These induced hematologic solid activating caspase-9 cascade, effectively lysed vitro mediating established their models. detected most tissues, neither bound or killed HLA-A2+ blood nor caused tissue damage tumor-free tumor-bearing HLA-A2-transgenic mice. Our study suggests may promising agent treat cancers.