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LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS

LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS
使用标记的单克隆抗体进行定位和治疗——模型系统
批准号:
3796502
负责人:
J SCHLOM
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至

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中文摘要
翻译
CC49是针对B72.3的“第二代”单克隆抗体,它与B72.3发生反应
英文摘要
CC49 is a "second generation" MAb to B72.3, which reacts with the pancarcinoma antigen TAG-72. CC49 has been shown to efficiently target human colon carcinoma xenografts and is currently being evaluated in both diagnostic and therapeutic clinical trials. We have described the construction and characterization of a recombinant single-chain Fv (sFv) of CC49. The sFv was shown to be a Mr 27,000 homogeneous entity which could be efficiently radiolabeled with 125-1 or 131-1. Metabolism studies in mice, using radiolabeled CC49 IgG, F(ab')2, Fab', and sFv, demonstrated an extremely rapid plasma and whole body clearance for the sFv. CC49 sFv plasma pharmacokinetic studies in rhesus monkeys also showed a very rapid plasma clearance. Tumor targeting studies with all four radiolabeled Ig CC49 forms, using the LS-174T human colon carcinoma xenograft model, revealed a much lower percentage injected dose/g tumor binding for the CC49 monomeric sFv and Fab' as compared to the dimeric F(ab')2 and intact IgG. However, tumor:normal tissue ratios (radiolocalization indices) for the sFv were comparable to or greater than those of the other Ig forms. The CC49 sFv may thus have utility in diagnostic and therapeutic applications for a range of human carcinomas. 177-Lutetium (177-Lu) is a member of the family of elements known as lanthanides or rare earths. We have demonstrated the first use of a 177-Lu-labeled immunoconjugate, 177-Lu-CC49, in an experimental therapy model for human carcinoma. 177-Lu-CC49 was shown to delay the growth of established LS-1 74T human colon carcinomas in athymic mice at a single dose of 50 mu-Ci. A single administration of 200 or 350 mu-Ci of 177-Lu-CC49 was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 mu-Ci of 177-Lu-CC49 (250 mu-Ci/week for 3 consecutive weeks) was well tolerated and this dose schedule was able to eliminate the growth of relatively large human colon tumor xenografts in 90% of the animals treated. The merits of the use of 177-Lu-labeled immunoconjugated (in particular, 177-Lu-CC49) should now be considered in terms of potential novel therapeutics for human carcinoma.
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CLINICAL TRIALS WITH RADIOLABELED ANTIBODIES
DESIGN & DEVELOPMENT OF RECOMBINANT VACCINES FOR CANCER IMMUNOTHERAPY
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
CLINICAL TRIALS WITH RADIOLABELED ANTIBODIES
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