Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin
Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin
复制标题
DOI：
10.1073/pnas.0406180101
复制
发表时间：
2004-10-12
影响因子：
11.1
通讯作者：
Casadevall, A
中科院分区：
文献类型：
--
作者：
Dadachova, E;Nosanchuk, JD;Casadevall, A
黑色素瘤是一种发病率不断上升的癌症，而转移性疾病几乎总是致命的。我们研究了利用黑色素结合单抗（6D2）靶向黑色素（一种细胞内黑色素细胞色素）向体内人类黑色素瘤细胞传递细胞毒性辐射的可行性。用1.5 mCi (1 Ci = 37 GBq) β -发射体188-铼（Re-188）标记的mAb 6132治疗携带MNT1色素的人黑色素瘤裸鼠，显示出抑制肿瘤生长和延长生存期的作用。mAb 6132结合肿瘤黑色素，与黑鼠正常黑色素化组织无交叉反应。黑色素靶向的机制涉及Ab与肿瘤细胞周转过程中释放的细胞外黑色素或具有透膜的垂死细胞结合。在这种方法中，从与黑色素结合的标记Ab发出的细胞毒性辐射可能通过“交叉火力”效应传递到邻近的活肿瘤细胞。我们的研究结果确定了用放射性标记抗体靶向肿瘤中死亡黑色素瘤细胞释放的黑色素以达到治疗效果的可行性。与传统的肿瘤抗原相比，黑色素是不溶性的，不易降解，并且可以在目标组织中积累，这表明治疗的效果可以随着后续治疗周期的增加而增加。
Melanoma is a cancer with a rising incidence, and metastatic disease is almost always lethal. We investigated the feasibility of targeting melanin, an intracellular melanocyte pigment, to deliver cytotoxic radiation to human melanoma cells in vivo by using a melanin-binding mAb (6D2). Nude mice bearing MNT1 pigmented human melanoma tumors were treated with mAb 6132 labeled with 1.5 mCi (1 Ci = 37 GBq) of the beta-emitter 188-Rhenium (Re-188) and manifested inhibition of tumor growth and prolonged survival. mAb 6132 bound tumor melanin and demonstrated no crossreactivity with normal melanized tissues in black mice. The mechanism of melanin targeting involved Ab binding to extracellular melanin released during tumor cell turnover or to dying cells with permeable membranes. In this approach, the cytotoxic radiation emanating from labeled Ab bound to melanin is presumably delivered by "crossfire" effect to the adjacent viable tumor cells. Our results establish the feasibility of targeting melanin released from dead melanoma cells in tumors with radiolabeled Abs to achieve a therapeutic effect. In contrast to conventional tumor antigens, melanin is insoluble, resistant to degradation, and can be expected to accumulate in targeted tissues, suggesting that the efficacy of therapy could increase with each subsequent treatment cycle.