title: Evaluation of a complementarity-determining region-grafted (humanized) anti-carcinoembryonic antigen monoclonal antibody in preclinical and clinical studies.
abstract: A complementarity-determining region-grafted (humanized) version of MN-14 (hMN-14), a high-affinity, anti-carcinoembryonic antigen (CEA) murine monoclonal antibody (mMAb), was selected from several clones that differed slightly in their framework composition. One clone was selected based on its similar binding affinity to CEA as that observed with mMN-14 MAb and its production yields. Targeting studies, using 131I-labeled humanized MN-14 (hMN-14)/125I-labeled mMN-14 IgG in GW-39 tumor-bearing nude mice, showed excellent tumor uptake and tumor: nontumor ratios, similar to the mMN-14. A pilot clinical imaging trial was initiated to determine the targeting, pharmacokinetics, and dosimetry for 131I-labeled hMN-14 IgG. Nineteen patients with advanced CEA-producing tumors were given 8 to 30 mCi (0.5 to 20.0 mg). Eleven patients also received 131I-labeled mMN-14 IgG for comparison. The biodistribution, tumor targeting, and pharmacokinetic behavior of the hMN-14 was similar to that seen with the mMN-14. The average time required to clear 50% of the radiolabeled hMN-14 from the blood and total body was 32.9 +/- 25.6 h and 109 +/- 73 h, respectively. Patients with elevated plasma CEA (i.e., > 200 ng/ml) had more than 30% of the labeled antibody complexed within 1 h after injection. In some of these patients, increased complexation resulted in enhanced metabolism of the antibody with more rapid clearance from the blood than that seen in patients with lower plasma CEA. The average radiation absorbed dose measured in 20 tumors (average weight, 204 +/- 205 g) in 14 patients was 7.6 +/- 5.3 cGy/mCi. Tumor: nontumor dose ratios were 2.5 +/- 1.6, 9.5 +/- 5.8, and 2.6 +/- 1.8 for the red marrow, total body, and liver, respectively. One patient, with a highly elevated human anti-mouse antibody response from a prior OncoScint study (murine B72.3 IgG), received 3 injections of the hMN-14 without an adverse experience, and showed no evidence of altered biodistribution characteristic of mMAb-human anti-mouse antibody interactions. An antibody response to hMN-14 (HAhMN14) was not detected in patients who received only the hMN-14 (as many as three injections), but in three patients who received two injections of the mMN-14, a HAhMN14 response was detected. With similar, excellent targeting properties as the mMN-14 and the potential for reduced immunogenicity, hMN-14 is an attractive candidate for further clinical imaging and therapy applications.
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D005260:Female; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000532:radiotherapy*; D009374:Neoplasms, Experimental / Q000532:radiotherapy; D010865:Pilot Projects; D016499:Radioimmunotherapy; D011877:Radionuclide Imaging
chemical_list: D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007135:Immunoglobulin Variable Region; D007457:Iodine Radioisotopes