Anti-Cancer Efficacy of Anti-CEA IgG3 in a Syngeneic Carcinoembryonix Antigen Tumor Model

Cho, Hyun Mi; Kim, Hae Jung; Cho, Mi Young; Shin, Seung Uon

Abstract

Development of antibody-based cancer therapies will be greatly facilitated if antibodies are better standardized in two fundamental issues that are specificity analysis of antibody reactivity and the detailed biodistribution and pharmacokinetic profile of antibodies. In the current endeavor we attempted to use an antibody binding specificity to target the tumor in a syngeneic carcinoembryonic antigen (CEA) tumor model. CEA, a 180 kDa glycoprotein, expressed at high levels on the surface of nearly all tumors of the gastrointestinal tract was used a potential target for antibody immunotherapy of gastrointestinal carcinomas. Using the CEA model antibody-based cancer therapy directed against CEA has been evaluated in a syngeneic animal model of disseminated disease. We constructed mouse/human chimeric anti-CEA IgG3, which has been evaluated for the specificity for CEA and the detailed biodistribution and pharmacokinetic profiles. Anti-CEA IgG3 heavy chain was expressed with the expected 180kDa molecular weight, assembled as H2L2 forms with a co-expressed mouse/human chimeric anti-CEA light chain, and were secreted. On FACS the purified anti-CEA IgG3 specifically recognized the mouse colon adenocarcinoma cell line MC-38 transduced with CEA (MCA32a), but not MC 38 without expressing CEA. After subcutaneous injection in C57BL/6 mice the half- lives of anti-CEA IgG3 and an irrelevant anti-dansyl IgG3 showed the bi-phasic kinetic patterns, and their pharmacokinetics of the distribution and the elimination were similar in mice. However, the biodistribution patterns of anti-CEA IgG3 were very different from those of anti-dansyl IgG3. Anti-dansyl IgG3 was mainly distributed into kidney until 72 hours, but anti-CEA IgG3 was slowly rernoved from blood and distributed into liver, kidney, spleen, and tumor. It is note worthy that anti- CEA IgG3 increased in targeting MCA32a tumor expressing human CEA by time, but the targeting to MC38 tumor was negligible. Thus, the increased targeting of anti- CEA IgG3 made MCA32a tumor grow slowly