Life science
Medical & healthcare, Drug development

Development of CAR-T cell therapy targeting cancer-specificantigen structures formed by post-translational changes
Department of Hematology and Oncology, Graduate School of Medicine
Professor Naoki Hosen
https://researchmap.jp/hnaoki

Life science

Abstract
We have isolated a new antibody that recognizes CD98hc, aubiquitously expressed protein, yet exhibits specific binding tomultiple myeloma (hereinafter referred to as “myeloma”). Remarkable advances have been made in its treatment of myeloma. Amongthem, antibody drugs are highly effective for myeloma, and recently, the development of various treatments with antibody-derivatives
such as CAR-T cells is extremely active. However, it is still difficult
to cure myeloma, and further identification of target antigens is desired. Among more than 10,000 anti-myeloma monoclonal antibodies, we identified R8H283 as a myeloma-specific mAb and foundthat R8H283 recognized CD98hc, which is also expressed in normal leukocytes. Normal leukocytes expressed CD98hc glycoforms
distinct from those expressed in MM cells, which may explain thelack of R8H283 reactivity in normal leukocytes. R8H283 exerted
anti-MM effects without damaging normal hematopoietic cells.
These findings suggest that R8H283 is a new source for mAbbased therapies against MM. In addition, our findings show thata cancer-specific conformational epitope in a ubiquitous protein,which cannot be identified by transcriptome or proteome analyses,
can be found by extensive screening of primary human tumor samples.

▍ Significance of the research and Future perspective
These results suggest that R8H283, which recognizes the multiple myeloma-specific antigen structure present in CD98hc, canbe used for new antibody therapy against myeloma or CAR-T celltherapy applying it.

▍ Background & Results
A monoclonal antibody drug that targets multiple myeloma cellsurface antigens has significantly improved the prognosis of myeloma patients. Furthermore, in recent years, the development ofvarious treatments with antibody-derivatives such as CAR-T cells
is progressing. However, it is still very difficult to cure myeloma.
Therefore, it is important to identify more therapeutic target antigens, but the search for genes and proteins specifically expressedin myeloma cells has already been extensively conducted all over
the world, making it extremely difficult to identify new therapeutictargets. We generated more than 10,000 clones of monoclonal
antibodies that bind to myeloma cells, and among them, we identified an antibody called R8H283 that binds to myeloma cells but
not to normal blood cells. Next, we clarified that the protein recognized by R8H283 is CD98hc. Curiously, although CD98hc is also
expressed on normal blood cells, R8H283 did not bind to normal
blood cells. We found that the attached N-glycans differ greatly
between CD98hc expressed on myeloma cells and CD98hc expressed on normal blood cells. Furthermore, R8H283 was foundto bind more strongly to cells expressing CD98hc with immature
N-glycans attached. These results suggest that the difference inN-glycosylation of CD98hc expressed in myeloma cells and normal blood cells may be responsible for the myeloma specificity of
the R8H283 antibody. Furthermore, in experiments using mice, weshowed that administration of R8H283 specifically eliminated myeloma cells without damaging normal cells.

P a t e n t
Hasegawa, Kana; Ikeda, Shunya; Yaga, Moto et al. Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous
protein CD98 heavy chain. Sci Transl Med 14:eaax7706, 2022. doi: 10.1126/scitranslmed.aax7706
Hosen, Naoki; Matsunaga, Yukiko; Hasegawa, Kana et al. The activated conformation of integrin beta7 is a novel multiple myeloma-specific target for CAR
T cell therapy. Nat Med 23:1436-1443, 2017. doi: 10.1038/nm.4431
https://www.med.osaka-u.ac.jp/pub/bldon/URL
http://www.ifrec.osaka-u.ac.jp/en/laboratory/naoki_hosen/
K e y w o r d cancer, multiple myeloma, CAR-T cell
Tr e a t i s e