Multiple Myeloma is a largely incurable cancer of plasma cells with an extremely poor prognosis. However, in a recent study published in Science Translational Medicine entitled “Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain”, scientists have discovered the CD98 heavy chain, a common component of amino acid transporters, may represent a promising monoclonal antibody for the treatment of multiple myeloma.
In this study, the researchers proposed a new method, which mainly involves extensive screening of monoclonal antibodies against primary human tumor samples in order to identify cancer-specific conformational epitopes on proteins that cannot be identified by transcriptome or proteome analysis.
Some patients with multiple myeloma often relapse with immune escape mutations, which makes cancer cells in the body resistant to therapy. Therefore, there is an urgent need for researchers to find new target antigens to develop a multi-targeted method to avoid immune escape and disease recurrence.
In previous studies, researchers focused on cancer-specific cell surface antigens through transcriptome or proteome analyses. However, these studies have missed the cancer-specific epitopes formed by protein covalency and enzymatic modification (i.e., post-translational modification), such as glycosylation or conformational changes. In order to expand the search for new target antigens, Hasegawa and his colleagues screened cancer-specific monoclonal antibodies and then analyzed the characteristics of their target-presenting antigens.
Researcher Kana Hasegawa said that by screening more than 10, 000 monoclonal antibodies against multiple myeloma cells, they identified R8H283, a special monoclonal antibody that recognizes the CD98 heavy chain protein (part of an amino acid transporter). Although the CD98 heavy chain exists in all cells, the antibody binds only to multiple myeloma cells. This selectivity reflects the different glycosylation patterns between normal cells and multiple myeloma cells.
In-depth analysis of R8H283 antibody revealed its specific binding to CD98 isomers rather than CD98 heavy chain monomers. Heterodimer complexes composed of CD98 heavy chain and light chain regulate the intake of amino acids needed for immunoglobulin production. Interestingly, the isomers of CD98 heavy chains in heterodimers present in normal leukocytes are different from those in multiple myeloma cells, which explains the lack of responsiveness of R8H283 to normal leukocytes. This also means that R8H283 antibodies exert anti-multiple myeloma effect without damaging normal host cells.
In order to evaluate the effectiveness of the R8H283 antibody in animal models, the researchers used a mouse multiple myeloma xenograft model and found that R8H283 injection prolonged the survival of mice, which may confirm that R8H283 can be used as a candidate drug for monoclonal antibody therapy for multiple myeloma.
