Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain.

Abstract

Cancer-specific cell surface antigens are ideal therapeutic targets for monoclonal antibody (mAb)-based therapy. Here, we report that multiple myeloma (MM), an incurable hematological malignancy, can be specifically targeted by an mAb that recognizes a ubiquitously present protein, CD98 heavy chain (hc) (also known as SLC3A2). We screened more than 10,000 mAb clones raised against MM cells and identified R8H283, an mAb that bound MM cells but not normal hematopoietic or nonhematopoietic cells. R8H283 specifically recognized CD98hc. R8H283 did not react with monomers of CD98hc; instead, it bound CD98hc in heterodimers with a CD98 light chain (CD98lc), a complex that functions as an amino acid transporter. CD98 heterodimers were abundant on MM cells and took up amino acids for constitutive production of immunoglobulin. Although CD98 heterodimers were also present on normal leukocytes, R8H283 did not react with them. The glycoforms of CD98hc present on normal leukocytes were distinct from those present on MM cells, which may explain the lack of R8H283 reactivity to normal leukocytes. R8H283 exerted anti-MM effects without damaging normal hematopoietic cells. These findings suggested that R8H283 is a candidate for mAb-based therapies for MM. In addition, our findings showed that a 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.

• Authors: Kana Hasegawa, Shunya Ikeda, Moto Yaga, Kouki Watanabe, Rika Urakawa, Akie Iehara, Mai Iwai, Seishin Hashiguchi, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Satoshi Yoshihara, Masahiro Manabe, Hiroyoshi Ichihara, Atsuko Mugitani, Yasutaka Aoyama, Takafumi Nakao, Asao Hirose, Masayuki Hino, Shiho Ueda, Katsuto Takenaka, Takashi Masuko, Koichi Akashi, Takahiro Maruno, Susumu Uchiyama, Shinji Takamatsu, Naoki Wada, Eiichi Morii, Shushi Nagamori, Daisuke Motooka, Yoshikatsu Kanai, Yusuke Oji, Tomoyoshi Nakagawa, Noriyuki Kijima, Haruhiko Kishima, Atsuyo Ikeda, Takayuki Ogino, Yasushi Shintani, Tateki Kubo, Emiko Mihara, Kosuke Yusa, Haruo Sugiyama, Junichi Takagi, Eiji Miyoshi, Atsushi Kumanogoh, Naoki Hosen
• Journal: Science translational medicine (Sci Transl Med) Vol. 14 Issue 632 Pg. eaax7706 (02 16 2022) ISSN: 1946-6242 [Electronic] United States
• PMID: 35171652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal

Topics

• Antibodies, Monoclonal (therapeutic use)
• Humans
• Multiple Myeloma