Identification of a new multiple myeloma-specific antigen as a target for CAR-T cell therapy
Naoki Hosen1, Kana Hasegawa1, Yukiko Matsunaga4, HaruoSugiyama2, Junichi Takagi4, Atsushi Kumanogoh3
Departments of 1Cancer Stem Cell Biology, 2Cancer Immunology, and 3Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, 4Institution of Protein Research, Osaka University
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 an MM-specific mAbs designated as MMG49 after screening more than 10,000 anti-MM mAb clones. Then, we identified the antigen recognized by MMG49 by an expression cloning method. Interestingly, expression of the antigen protein for MMG49 was not specific to MM cells, suggesting that this mAb recognized an MM-specific epitope formed by post-translational events. Finally, we showed that CAR-T cells derived from MMG49 could reduce tumor burden in MM-xenograft models, but did not damage normal hematopoietic cells. These results not only demonstrate that MMG49-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.
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