A universal pretargeting system for cancer detection and therapy using bispecific antibody.
A universal pretargeting system for cancer detection and therapy using bispecific antibody.
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发表时间：
2003-01
期刊：
影响因子：
11.2
通讯作者：
R. Sharkey;W. Mcbride;H. Karacay;Ken Chang;G. Griffiths;H. Hansen;D. Goldenberg
中科院分区：
文献类型：
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作者：
R. Sharkey;W. Mcbride;H. Karacay;Ken Chang;G. Griffiths;H. Hansen;D. Goldenberg
多步靶向系统代表了用于诊断和治疗应用的使用直接放射性标记抗体的靶向系统的高度选择性替代方案。本文描述了柔性双特异性抗体（bsMAb）多步预靶向系统，其潜在地可以被开发用于与多种不同的成像剂或治疗剂一起使用。该系统的灵活性是基于使用针对组胺-琥珀酰-甘氨酸（HSG）的抗体和开发含有HSG残基的肽。用1，4，7，10-四氮杂环十二烷-N，N '，N”，N“'-四乙酸螯合111 In、90 Y或177 Lu，或用锝/锝螯合物合成含HSG的肽。可以以避免纯化需要的简便方式将肽放射性标记至高比活性。在携带人结肠肿瘤异种移植物的裸鼠中的体内研究表明，放射性标记的肽从体内快速清除，在肿瘤或正常组织中的保留最小。对于预靶向，这些肽与由抗HSG Fab'组成的bsMAb组合使用，所述抗HSG Fab'与抗癌胚抗原或抗结肠特异性抗原-β抗体的Fab'共价偶联以提供肿瘤靶向能力。当在bsMAb的预靶向剂量后1-2天施用放射性标记的肽时，放射性标记的肽的肿瘤摄取比单独使用肽所观察到的增加多达28-175倍，并且在肽注射的仅仅3小时内肿瘤：非肿瘤比率超过2：1至8：1，这比在同一时间使用直接放射性标记的99 mTc-抗抗癌胚抗原Fab'所观察到的肿瘤：非肿瘤比率有显著改善。抗结肠特异性抗原-p x anti-HSG F（ab '）2 bsMAb在肿瘤中具有最高和最长的保留，并且当与111 In标记的肽组合使用时，治疗性放射性核素（例如90 Y和177 Lu）的辐射剂量估计表明，在对正常组织的可耐受的辐射暴露下，预期具有抗肿瘤作用。这些结果表明，这种多步骤的预靶向系统具有诊断成像和治疗潜力。
Multistep targeting systems represent highly selective alternatives to targeting systems using directly radiolabeled antibodies for diagnostic and therapeutic applications. A flexible bispecific antibody (bsMAb) multistep, pretargeting system that potentially can be developed for use with a variety of different imaging or therapeutic agents is described herein. The flexibility of this system is based on use of an antibody directed against histamine-succinyl-glycine (HSG) and the development of peptides containing the HSG residue. HSG-containing peptides were synthesized with either 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid for the chelation of 111In, 90Y, or 177Lu, or a technetium/rhenium chelate. The peptides can be radiolabeled to a high specific activity in a facile manner that avoids the need for purification. In vivo studies in nude mice bearing human colon tumor xenografts showed that the radiolabeled peptides cleared rapidly from the body with minimal retention in tumor or normal tissues. For pretargeting, these peptides were used in combination with a bsMAb composed of the anti-HSG Fab' that was covalently coupled with the Fab' of either an anticarcinoembryonic antigen or an anticolon-specific antigen-p antibody to provide tumor targeting capability. When the radiolabeled peptides were administered 1-2 days after a pretargeting dose of the bsMAbs, tumor uptake of the radiolabeled peptides increased as much as 28-175-fold over that seen with the peptides alone with tumor:nontumor ratios exceeding 2:1 to 8:1 within just 3 h of the peptide injection, which was a marked improvement over the tumor:nontumor ratios seen with a directly radiolabeled 99mTc-anti-anticarcinoembryonic antigen Fab' at this same time. The anticolon-specific antigen-p x anti-HSG F(ab')2 bsMAb had the highest and longest retention in the tumor, and when used in combination with the 111In-labeled peptide, radiation dose estimates for therapeutic radionuclides, such as 90Y and 177Lu, suggested that antitumor effects would be expected with tolerable radiation exposure to the normal tissues. These results suggest that this multistep, pretargeting system has diagnostic imaging and therapeutic potential.