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.
