Sharkey R M, Motta-Hennessy C, Gansow O A, Brechbiel M W, Fand I, Griffiths G L, Jones A L, Goldenberg D M
Center For Molecular Medicine and Immunology, University of Medicine and Dentistry, Newark, NJ 07103.
Int J Cancer. 1990 Jul 15;46(1):79-85. doi: 10.1002/ijc.2910460116.
Our previous studies with a 90Y-labelled antibody against carcinoembryonic antigen (CEA) conjugated to the cyclic anhydride-DTPA (CA-DTPA) indicated that the accretion of 90Y in the bone may limit the application of 90Y-labelled antibodies for therapy. In this report, we have compared the tumor targeting of CA-DTPA-conjugated antibody to antibody conjugated with 4 isothiocyanatobenzyl (ITC-Bz) derivatives of DTPA in nude mice bearing a human colonic tumor xenograft. In biodistribution studies using an 111In-labelled anti-CEA murine monoclonal antibody (MAb), the CA-DTPA-conjugated MAb showed lower tumor uptake, faster blood clearance, and higher accretion in the liver than any of the 4 ITC-Bz-DTPA-conjugated MAbs. There were smaller differences among the 4 ITC-Bz-DTPA conjugates. Whole-body autoradiography of animals given 90Y-MAb prepared with the CA-DTPA or the ITC-Bz-DTPA showed less radioactivity in the bone with the ITC-Bz-DTPA-MAb than the CA-DTPA-MAb. 90Y uptake in the bone corresponded with regions of low proliferative activity as defined by 3H-labelled thymidine, suggesting that the 90Y was in the cortex rather than the marrow. These studies clearly show an advantage of the ITC-Bz-DTPA derivatives for 90Y and 111In labelling of MAbs.
我们之前使用与环状酸酐 - DTPA（CA - DTPA）偶联的90Y标记抗癌胚抗原（CEA）抗体的研究表明，90Y在骨骼中的积聚可能会限制90Y标记抗体在治疗中的应用。在本报告中，我们比较了CA - DTPA偶联抗体与用DTPA的4种异硫氰酸苯甲基（ITC - Bz）衍生物偶联的抗体在携带人结肠肿瘤异种移植的裸鼠中的肿瘤靶向性。在使用111In标记的抗CEA鼠单克隆抗体（MAb）的生物分布研究中，CA - DTPA偶联的MAb与4种ITC - Bz - DTPA偶联的MAb相比，显示出较低的肿瘤摄取、更快的血液清除率和更高的肝脏积聚。4种ITC - Bz - DTPA偶联物之间的差异较小。用CA - DTPA或ITC - Bz - DTPA制备的90Y - MAb给药动物的全身放射自显影显示，与CA - DTPA - MAb相比，ITC - Bz - DTPA - MAb在骨骼中的放射性较低。骨骼中90Y的摄取与3H标记胸腺嘧啶核苷所定义的低增殖活性区域相对应，这表明90Y存在于皮质而非骨髓中。这些研究清楚地表明了ITC - Bz - DTPA衍生物在90Y和111In标记MAb方面的优势。
