MONOCLONAL ANTIBODIES DEFINE CARCINOMA ASSOCIATED AND DIFFERENTIATION ANTIGENS

在单克隆抗体的表征方面取得了进展

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.