Abstract 2821: Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers

Abstract

Abstract Immunotherapy is a promising option for cancer treatment. Targeted immunotherapy with monoclonal antibodies (mAbs) is an effective and safe method for the treatment of malignancies. In recent years, efforts have been made to identify potential therapeutic mAbs by defining alternative or novel target antigens. We reported that Dickkopf-1 (DKK1) is a good target for immunotherapy of human cancers based on its wide expression in different cancers but not in normal tissues. As DKK1 is a secreted protein, mAbs directly binding to DKK1 may have limited effects on cancer cells in vivo. Our previous studies demonstrated that DKK1 peptide (such as P20 and P66v, which bind with HLA-A*0201 (HLA-A2) molecule) specific cytotoxic T cells specifically kill myeloma and other cancer cells that express DKK1 and HLA-A2, but not HLA-A2+ normal cells, indicating that DKK1+ tumor cells naturally express these peptides, in the context of HLA-A2 molecules, on their surface. To develop cancer therapeutic antibodies, DKK1 peptide P20-HLA-A2 monomer was synthesized and used to immunize mice. Hybridomas secreting mAbs recognizing cell surface-expressed DKKl P20-HLA-A2 complex (DKK1-A2) were obtained and analyzed. In this study, we generated novel (DKK1-A2) mAbs recognizing DKK1 (P20) peptide in the context of human HLA-A*0201 (HLA-A2) molecules (DKK1-A2 complexes) that are naturally expressed by HLA-A2+DKK1+ cancer cells. These mAbs bound to HLA-A2+DKK1+ hematologic (myeloma, lymphoma, and leukemia) and solid (breast, pancreatic, and prostate) cancer cells and directly induced apoptosis in the cancer cells by activating the caspase-9 cascade. DKK1-A2 mAbs also effectively lysed cancer cells in vitro by mediating CDC and ADCC activities. Furthermore, DKK1-A2 mAbs were therapeutic against established hematologic and solid cancers in their xenograft mouse models. To enhance the therapeutic efficacy of DKK1-A2 mAbs, we investigated the effect of combination treatment of DKK1-A2 mAbs with lenalidomide. Our results showed that there is an additive therapeutic effect between DKK1-A2 mAbs and lenalidomide in vivo, underscoring a potential clinical development strategy for combining DKK1-A2 mAb with lenalidomide to treat cancer patients. As DKK1 is not detected in most human tissues, DKK1-A2 mAbs did not bind to or kill HLA-A2+ blood cells in vitro nor caused tissue damage in vivo in tumor-free or tumor-bearing HLA-A2-transgenic mice. Thus, our study suggests that DKK1-A2 mAbs may be a promising therapeutic agent to treat human cancers and warrants further preclinic studies to determine their translatability to clinic. Citation Format: Jianfei Qian, Wang Qiang, Liuling Xiao, Wei Xiong, Miao Xian, Chuanchao Zhang, Yabo Li, Qing Yi. Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2821.