Description

Identification of a new multiple myeloma-specific antigen as a target for monoclonal antibody therapy

Kana Hasegawa¹, Haruo Sugiyama², Atsushi Kumanogoh³, Naoki Hosen^1*

Department of ¹Cancer Stem Cell Biology, ²Cancer Immunology, and ³Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine

*Corresponding author

Cancer-specific cell surface antigens are ideal targets for therapies using monoclonal antibodies (mAbs). 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 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 R8H283 after screening more than 10,000 anti-MM mAb clones. Then, we identified the antigen recognized by R8H283 by an expression cloning method. Interestingly, expression of the antigen protein for R8H283 was not specific to MM cells, and its expression was broadly detected when examined with other antibodies recognizing the protein. Endoplasmic reticulum (ER) stress, which is detected at high levels in most MM cells, enhanced the expression of the R8H283 epitope. Finally, we showed that treatment with R8H283 could reduce tumor burden in MM-xenograft models, but did not damage normal hematopoietic cells. These results not only demonstrate that R8H283 is a promising mAb for MM treatment, but also suggest that other cell surface antigens appearing under ER stress, which occurred in several types of cancers, may be missed in the previous screens.