LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS
LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS
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
关键词:
Macaca mulatta antitumor antibody athymic mouse carcinoma clearance rate colon neoplasms genetic manipulation immunoconjugates immunoglobulin structure monoclonal antibody neoplasm /cancer immunodiagnosis neoplasm /cancer immunotherapy neoplasm /cancer radiation therapy neoplasm /cancer transplantation nonhuman therapy evaluation pharmacokinetics radiation therapy dosage radionuclides rare earth element tumor antigens
中文摘要
CC49是针对B72.3的"第二代"单克隆抗体,其与B72.3反应。
泛癌抗原TAG-72。 CC49已被证明有效靶向
人结肠癌异种移植物,目前正在评估这两个
诊断和治疗临床试验。 我们已经描述了
重组单链抗体(sFv)的构建和表征
CC49的 sFv显示为Mr 27,000的同质实体,
可以有效地用125 - 1或131 - 1进行放射性标记。 代谢
使用放射性标记的CC49 IgG、F(ab ')2、Fab'和sFv在小鼠中进行的研究,
证明了对这些药物的血浆和全身清除速度极快,
sFv。 在恒河猴中的CC49 sFv血浆药代动力学研究也
显示出非常快的血浆清除率。 所有肿瘤靶向研究
四种放射性标记的IG CC 49形式,使用LS-174 T人结肠癌
异种移植模型,显示出低得多的百分比注射剂量/g肿瘤
CC49单体sFv和Fab '与二聚体sFv和Fab'的结合
F(ab ')2和完整IgG。 然而,肿瘤:正常组织比
sFv的放射性定位指数(放射性定位指数)与
而不是其他IG形式。 因此,CC49 sFv可以在免疫治疗中具有实用性。
用于一系列人类癌症的诊断和治疗应用。
177-镥(177-Lu)是元素家族中的一员,
镧系元素或稀土元素。 我们已经展示了第一次使用
177-Lu标记的免疫缀合物,177-Lu-CC 49,在实验性治疗中
人癌模型。177-Lu-CC49显示出延迟
在无胸腺小鼠中建立的LS-1 74T人结肠癌,
剂量为50 μ Ci。 单次给予200或350 μ Ci的
177-Lu-CC49显示在77天内消除已建立的肿瘤。
MAb给药后的观察期。 剂量分割
实验表明,至少750 μ Ci的177-Lu-CC 49(250
μ Ci/周,连续3周)的耐受性良好,
时间表能够消除相对较大的人类结肠的生长
在90%的治疗动物中肿瘤异种移植物。 使用的优点
177-Lu标记的免疫缀合物(特别是177-Lu-CC49)现在应
被认为是潜在的新的治疗方法,
carcinoma.
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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会议论文
CLINICAL TRIALS WITH RADIOLABELED ANTIBODIES
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批准号:4691891
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
DESIGN & DEVELOPMENT OF RECOMBINANT VACCINES FOR CANCER IMMUNOTHERAPY
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批准号:6100774
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3813325
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
CLINICAL TRIALS WITH RADIOLABELED ANTIBODIES
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批准号:3939339
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3939256
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3916281
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
DESIGN & DEVELOPMENT OF RECOMBINANT VACCINES FOR CANCER IMMUNOTHERAPY
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批准号:6160874
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
ANTI-CARCINOMA MONOCLONAL ANTIBODIES CLINICAL TRIALS
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批准号:3813404
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
CLINICAL UTILITY OF MONOCLONAL ANTIBODIES AND RECOMBINANT IMMUNOGLOBULIN FORMS
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批准号:5200920
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
ANTI-CARCINOMA MONOCLONAL ANTIBODIES CLINICAL TRIALS
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批准号:3808558
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3808494
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
CLINICAL TRIALS WITH RADIOLABELED ANTIBODIES
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批准号:3963062
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3752006
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3774291
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
CLINICAL TRIALS WITH RADIOLABELED ANTIBODIES
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批准号:3916368
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3796433
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS
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批准号:3962970
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
MONOCLONAL ANTIBODIES REACTIVE WITH HUMAN MAMMARY AND COLON CARCINOMA CELLS
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批准号:4691788
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
DESIGN & DEVELOPMENT OF RECOMBINANT VACCINES FOR CANCER IMMUNOTHERAPY
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批准号:2468427
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项目类别:
-
资助金额:$0.0万
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财政年份:--
-
负责人:J SCHLOM
-
依托单位:
LOCALIZATION AND THERAPY USING LABELED MONOCLONAL ANTIBODIES--MODEL SYSTEMS
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批准号:3808556
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项目类别:
-
资助金额:$0.0万
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财政年份:--
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负责人:J SCHLOM
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依托单位:
海外基金