MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS

单克隆抗体的特性研究已取得进展 （MAbs）的三种癌相关抗原和潜在的用途， 这些单克隆抗体在一系列癌症的诊断和治疗中的应用。的 三种抗原是（a）TAG-72，一种高分子量粘蛋白，在大肠杆菌中表达， 胃肠道、乳腺、卵巢、子宫内膜、前列腺和非小细胞肺癌 细胞肺癌，其被MAb B72.3、GC 49和CC 83识别;（B） 癌胚抗原（CEA）a 180，000 D gp，表达于 胃肠道、乳腺和非小细胞肺癌， 被MAb COL-1至15识别的D gp，和（c）48，000 D gp表达于 结肠癌和正常结肠，其被MAb D 612识别。(I)到 检验高亲和力单克隆抗体是否具有更大的 治疗效果，三种放射性标记的抗肿瘤活性 分析人结肠癌异种移植物模型中的TAG-72 MAb; CC 49和CC 83具有比B72.3高8倍和10倍的亲和力， 分别在检查的所有剂量下，较高亲和力的MAb显示出 更大的抗肿瘤作用。一种新的放射免疫偶联物--镥 在该相同的实验模型中分析（177 Lu）标记的CC 49。177Lu 是一种稀土镧系元素，具有独特的放射性药物特性。 观察到强的抗肿瘤作用，具有最小的毒性。单个 从单克隆抗体CC 49构建了单链抗体，并显示出良好的肿瘤抑制作用。 靶向特性，以及快速血浆和全身清除， 异种移植模型定量放射自显影分析显示， sFv穿透肿瘤非常迅速， 与完整的IgG相比是均匀的。还确定， 177 Lu标记的sFv与碘标记的sFv相比具有非常不同的代谢谱 sFv CC49。这些研究对设计潜在的 临床试验应用CA 72 -4免疫测定法检测TAG-72 癌症患者血清中的抗原，结果表明， TAG-72和19-9抗原水平的分析显著增加了 胃癌患者的鉴别，同时联合使用 检测TAG-72和CEA的测定增加了结直肠癌的阳性率， 癌症患者，在这两种情况下，没有实质性增加假 肯定的：第(Il)使用一系列用CEA转导的细胞系， 相关基因作为对照，结果表明，除了G1癌， CEA在大约50%的人乳腺癌和70%的人乳腺癌中表达。 非小细胞肺癌抗CEA MAb COL-1的进一步评价 表明131 l-COL-1可以有效地靶向和消除生长 在异种移植模型中建立的人类肿瘤。(III)抗原 进一步表征了MAb D 612识别的细胞。(IV)许多 使用MAb CG 49、COL-1和 第612章已经完成或正在进行中

Progress has been made in the characterization of monoclonal antibodies (MAbs) to three carcinoma associated antigens and the potential use of these MAbs in both the diagnosis and therapy of a range of carcinomas. The three antigens are (a) TAG-72, a high molecular weight mucin expressed in gastrointestinal, breast, ovarian, endometrial, prostate and non-small cell lung cancers, which is recognized by MAbs B72.3, GC49 and CC83; (b) carcinoembryonic antigen (CEA) a 180,000 D gp, expressed in gastrointestinal, breast and non-small cell lung cancer, which is recognized by MAbs COL-1 through 15 and (c) a 48,000 D gp expressed on colon carcinomas and normal colon, which is recognized by MAb D612. (I) To test the hypothesis of whether high affinity MAbs have a greater therapeutic efficacy, the anti-tumor activity of three radiolabeled anti- TAG-72 MAbs in a human colon cancer xenograft model was analyzed; MAbs CC49 and CC83 have a 8-fold and 10-fold higher affinity than B72.3, respectively. At all doses examined, the higher affinity MAbs demonstrated greater anti-tumor effects. A novel radioimmunoconjugate, lutetium (177Lu)-labeled CC49 was analyzed in this same experimental model. 177Lu is a rare earth lanthanide with unique radiopharmaceutical properties. Strong anti-tumor effects were observed with minimal toxicity. A single chain Fv has been constructed from MAb CC49 and has shown good tumor targeting properties, and rapid plasma and whole body clearance in a xenograft model. Quantitative autoradiographic analyses revealed that penetration through tumors with the sFv was extremely rapid and more homogeneous as compared to intact IgG. It has also been determined that a 177Lu-labeled sFv had a much different metabolic profile than iodinated sFv CC49. These studies have implications in the design of potential clinical trials. Employing the CA72-4 immunoassay to detect the TAG-72 antigen in the serum of cancer patients, it was shown that combined analyses of TAG-72 and the 19-9 antigen levels significantly increased the identification of patients with gastric cancer, while combined use of assays to detect TAG-72 and CEA increased positive rates for colorectal cancer patients, in both cases with no substantial increase in false positive. (Il) Using a series of cell lines transduced with the CEA and related genes as controls, it was shown that in addition to G1 carcinomas, CEA is expressed in approximately 50% of human breast cancers and 70% of non-small cell lung cancers. Further evaluation of the anti-CEA MAb COL-1 revealed that 131l-COL-1 could efficiently target and eliminate the growth of established human tumors in a xenograft model. (III) The antigen recognized by MAb D612 was further characterized. (IV) Numerous collaborative Phase I and Il clinical trials with MAbs CG49, COL-1 and D612 have been completed or are in progress.