Burton Jack D, Ely Scott, Reddy Praveen K, Stein Rhona, Gold David V, Cardillo Thomas M, Goldenberg David M
Center for Molecular Medicine and Immunology and Garden State Cancer Center, Belleville, New Jersey 07109, USA.
Clin Cancer Res. 2004 Oct 1;10(19):6606-11. doi: 10.1158/1078-0432.CCR-04-0182.
CD74 (HLA-DR-associated invariant chain) plays a role in antigen presentation. In addition to its expression on antigen-presenting cells, it is expressed by carcinomas of renal, lung, gastric, and thymic origin and by certain sarcomas. The restricted expression of CD74 by normal tissues and its very rapid internalization make CD74 an attractive therapeutic target for both cancer and immunologic diseases. Preclinical efficacy of anti-CD74 monoclonal antibody (mAb) therapy has been demonstrated in B-lymphoma models. Because there are few validated antigenic targets in multiple myeloma, CD74 expression was examined.
CD74 expression was assessed by immunohistochemistry in bone marrow biopsies of known multiple myeloma cases. Its expression was measured by flow cytometry in multiple myeloma lines, and CD74 mRNA expression was determined by reverse transcription-PCR. In addition, the in vitro antiproliferative effect of LL1 mAb was evaluated on a CD74+ multiple myeloma cell line using a [3H]thymidine incorporation assay.
CD74 expression was observed in 19 of 22 cases of multiple myeloma, with most expressing moderate to high levels in the majority of malignant plasma cells. CD74 was expressed by most multiple myeloma cell lines, as was CD74 mRNA, at levels mirroring CD74 protein. Also, unlabeled LL1 mAb mediated in vitro growth inhibition of a CD74+ multiple myeloma cell line.
CD74 expression is frequent in multiple myeloma, with predominant expression by the malignant plasma cells. Because anti-CD74 mAbs internalize very rapidly and LL1 mAb has shown efficacy in B-lymphoma models, CD74 represents a novel and promising target for treatment of multiple myeloma. Therefore, LL1 mAb is well suited as a carrier of radionuclides, drugs, or toxins, and also has activity as an unlabeled mAb, thereby supporting its development for this unmet need in cancer therapy.
CD74（HLA - DR相关恒定链）在抗原呈递中发挥作用。除了在抗原呈递细胞上表达外，它还在肾、肺、胃和胸腺来源的癌以及某些肉瘤中表达。CD74在正常组织中的限制性表达及其非常快速的内化作用，使其成为癌症和免疫疾病有吸引力的治疗靶点。抗CD74单克隆抗体（mAb）治疗在B淋巴瘤模型中已显示出临床前疗效。由于多发性骨髓瘤中经过验证的抗原靶点很少，因此对CD74表达进行了检测。
通过免疫组织化学评估已知多发性骨髓瘤病例骨髓活检中CD74的表达。通过流式细胞术检测多发性骨髓瘤细胞系中CD74的表达，并通过逆转录 - PCR测定CD74 mRNA的表达。此外，使用[3H]胸苷掺入试验评估LL1 mAb对CD74 + 多发性骨髓瘤细胞系的体外抗增殖作用。
在22例多发性骨髓瘤病例中的19例中观察到CD74表达，大多数在大多数恶性浆细胞中表达中度至高表达水平。大多数多发性骨髓瘤细胞系表达CD74，CD74 mRNA也表达，其水平与CD74蛋白水平一致。此外，未标记的LL1 mAb介导了对CD74 + 多发性骨髓瘤细胞系的体外生长抑制。
CD74表达在多发性骨髓瘤中很常见，主要由恶性浆细胞表达。由于抗CD74 mAb非常快速地内化，并且LL1 mAb在B淋巴瘤模型中已显示出疗效，CD74代表了治疗多发性骨髓瘤的一个新的有前景的靶点。因此，LL1 mAb非常适合作为放射性核素、药物或毒素的载体，并且作为未标记的mAb也具有活性，从而支持其针对癌症治疗中这一未满足需求的开发。
