Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain
Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain
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DOI：
10.1126/scitranslmed.aax7706
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发表时间：
2022-02-16
影响因子：
17.1
通讯作者：
Hosen, Naoki
中科院分区：
文献类型：
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作者：
Hasegawa, Kana;Ikeda, Shunya;Hosen, Naoki
肿瘤特异性细胞表面抗原是基于单克隆抗体（mAb）的治疗的理想治疗靶点。在这里，我们报告了多发性骨髓瘤（MM），一种无法治愈的血液系统恶性肿瘤，可以通过识别普遍存在的蛋白质CD 98重链（hc）（也称为SLC 3A 2）的mAb特异性靶向。我们筛选了超过10，000个针对MM细胞的mAb克隆，并鉴定了R8 H283，这是一种结合MM细胞但不结合正常造血或非造血细胞的mAb。R8 H283特异性识别CD 98 hc。R8 H283不与CD 98 hc的单体反应;相反，它与CD 98轻链（CD 98 lc）结合成异二聚体，CD 98 lc是一种作为氨基酸转运蛋白的复合物。CD 98异源二聚体在MM细胞上丰富，并摄取氨基酸用于组成性产生免疫球蛋白。虽然CD 98异源二聚体也存在于正常白细胞上，但R8 H283不与它们反应。存在于正常白细胞上的CD 98 hc的糖型与存在于MM细胞上的糖型不同，这可以解释R8 H283对正常白细胞缺乏反应性。R8 H283具有抗MM作用，而不损害正常造血细胞。这些研究结果表明，R8 H283是一个候选的单克隆抗体为基础的治疗MM。此外，我们的研究结果表明，癌症特异性构象表位在一个普遍存在的蛋白质，这不能通过转录组或蛋白质组分析确定，可以发现通过广泛的筛选原发性人类肿瘤样本。
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.