Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu.
Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu.
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DOI：
10.1038/bjc.1998.233
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发表时间：
1998-05
影响因子：
8.8
通讯作者：
Marks, J D
中科院分区：
文献类型：
--
作者：
Adams, G P;Schier, R;McCall, A M;Crawford, R S;Wolf, E J;Weiner, L M;Marks, J D
单链抗体（scFv）分子在荷瘤小鼠中表现出高度特异性的肿瘤靶向特性。然而，由于其较小的尺寸和单价结合，保留在肿瘤中的放射性标记的scFv的量限制了其治疗应用。双抗体是基于二聚抗体的分子，其由两个以二价方式结合抗原的非共价缔合的scFv组成。在体外，通过表面等离子体共振生物传感器测量，由抗HER 2/neu（c-erbB-2）scFv C6.5产生的双抗体显示出比C6.5 scFv高约40倍的对HER 2/neu的亲和力，并且与SK-0 V-3细胞表面上的抗原的结合显著延长（t1/2细胞表面保留> 5小时vs 5分钟）。在SK-OV-3荷瘤scid小鼠中，放射性碘标记的C6.5双抗体显示了肿瘤定量保留和特异性的高度有利平衡。早在静脉内给药后4小时，肿瘤中保留的双抗体（10%ID g（-1））显著多于血液（6.7%ID ml（-1））或正常组织（肝脏，2.8%ID g（-1）;肺，7.1%ID g（-1）;肾脏，5.2%ID g（-1））。在接下来的20小时内，血液和大多数组织中的含量下降了约10倍，而肿瘤保留了6.5%ID g（-1）或其4小时值的约三分之二。相比之下，放射性碘标记的C6.5 scFv单体的24小时肿瘤保留仅为1%ID g（-1）。当在72小时研究过程中检查双抗体保留并测定累积曲线下面积（AUC）值时，发现所得肿瘤-器官AUC比上级先前报道的其它单价或二价scFv分子的那些。总之，双抗体形式为C6.5分子提供了独特的体外和体内靶向优势，并有望作为治疗剂的递送载体。
Single-chain Fv (scFv) molecules exhibit highly specific tumour-targeting properties in tumour-bearing mice. However, because of their smaller size and monovalent binding, the quantities of radiolabelled scFv retained in tumours limit their therapeutic applications. Diabodies are dimeric antibody-based molecules composed of two non-covalently associated scFv that bind to antigen in a divalent manner. In vitro, diabodies produced from the anti-HER2/neu (c-erbB-2) scFv C6.5 displayed approximately 40-fold greater affinity for HER2/neu by surface plasmon resonance biosensor measurements and significantly prolonged association with antigen on the surface of SK-OV-3 cells (t1/2 cell surface retention of > 5 h vs 5 min) compared with C6.5 scFv. In SK-OV-3 tumour-bearing scid mice, radioiodinated C6.5 diabody displayed a highly favourable balance of quantitative tumour retention and specificity. By as early as 4 h after i.v. administration, significantly more diabody was retained in tumour (10 %ID g(-1)) than in blood (6.7 %ID ml(-1)) or normal tissue (liver, 2.8 %ID g(-1); lung, 7.1 %ID g(-1); kidney, 5.2 %ID g(-1)). Over the next 20 h, the quantity present in blood and most tissues dropped approximately tenfold, while the tumour retained 6.5 %ID g(-1) or about two-thirds of its 4-h value. In contrast, the 24-h tumour retention of radioiodinated C6.5 scFv monomer was only 1 %ID g(-1). When diabody retentions were examined over the course of a 72-h study and cumulative area under the curve (AUC) values were determined, the resulting tumor-organ AUC ratios were found to be superior to those previously reported for other monovalent or divalent scFv molecules. In conclusion, the diabody format provides the C6.5 molecule with a distinct in vitro and in vivo targeting advantage and has promise as a delivery vehicle for therapeutic agents.