Identification of New Multiple Myeloma-Specific Cell Surface Antigens As Immunotherapeutic Targets

Cancer-specific cell surface antigens are ideal targets for therapies using monoclonal antibodies (mAbs) and their derivatives, such as chimeric antigen receptor (CAR)-T cells. However, such antigens are not likely to remain unidentified following extensive searching by transcriptome or proteome analyses. However, we hypothesized that cancer-specific antigens formed by post-translational events, such as glycosylation, complex formation, or conformational changes, might have been missed in previous screens. Such antigens could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens recognized by these mAbs. To test our hypothesis, we applied this strategy to identify novel therapeutic targets specific for multiple myeloma (MM), a major hematological cancer. We first identified two MM-specific mAbs designated as MMG49 or R8H283 after screening more than 10,000 anti-MM mAb clones. Then, we identified the antigens recognized by these mAbs by an expression cloning method. Interestingly, genes identified as antigens for both mAbs were not specific to MM cells, suggesting that both mAbs recognize MM-specific epitopes formed by post-translational events. Finally, we showed that these mAbs or CAR-T cells derived from them could reduce tumor burden in MM-xenograft models, but did not damage normal hematopoietic cells. These results not only demonstrate that these mAb or CAR-T cell therapy is promising for MM, but also suggest that MM-specific immunotherapetic target antigens formed by post translational events may be still missed.