Although all cells express the key CD98 amino acid transporter, Hasegawa et al. screened 10,000 hybridomas to find a mAb which bound a glyco-epitope expressed selectively on human MM cells comprising the extracellular domain of CD98 heavy chain (hc) dimerized with CD98 light chain. The epitope was increased by in vitro exposure to bortezomib, a drug widely used to treat MM. CD98hc expression was essential for MM cell proliferation in vitro and in mice. The mAb mediated ADCC and CDC of MM, but not normal hematopoietic cells in vitro without reducing cell surface CD98hc expression, and prolonged host survival in mouse MM models.
Contributed by Paula Hochman
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.
Author Info: (1) Laboratory of Cellular Immunotherapy, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. (2) Department of Functional Dia
Author Info: (1) Laboratory of Cellular Immunotherapy, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. (2) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (3) Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (4) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (5) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (6) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (7) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (8) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (9) Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (10) Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (11) Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (12) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (13) Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (14) Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (15) Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (16) Department of Hematology, Hyogo College of Medicine, Hyogo 663-8501, Japan. (17) Department of Hematology, Osaka General Hospital of West Japan Railway Company, Osaka 545-0053, Japan. (18) Department of Hematology, Fuchu Hospital, Osaka 594-0076, Japan. (19) Department of Hematology, Fuchu Hospital, Osaka 594-0076, Japan. (20) Department of Hematology, Fuchu Hospital, Osaka 594-0076, Japan. (21) Department of Hematology, Osaka City General Hospital, Osaka 534-0021, Japan. (22) Department of Hematology and Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan. (23) Department of Hematology and Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan. (24) Cell Biology Laboratory, School of Pharmacy, Kindai University, Osaka 577-8502, Japan. (25) Department of Hematology, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan. (26) Cell Biology Laboratory, School of Pharmacy, Kindai University, Osaka 577-8502, Japan. (27) Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. (28) Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan. (29) Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan. (30) Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (31) Department of Pathology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (32) Department of Pathology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (33) Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan. (34) Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan. (35) Department of Bio-system Pharmacology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (36) Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (37) Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (38) Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (39) Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (40) Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (41) Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (42) Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (43) Department of Plastic Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (44) Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan. (45) Stem Cell Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. (46) Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (47) Laboratory for Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan. (48) Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. (49) Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. (50) Laboratory of Cellular Immunotherapy, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan.
