In Vitro and In Vivo Pharmacology and Pharmacokinetics of a Human Engineered™ Monoclonal Antibody to Epithelial Cell Adhesion Molecule

• Main Authors: W. Steve Ammons, Robert J. Bauer, Arnold H. Horwitz, Zhi J. Chen, Eddie Bautista, Harry H. Ruan, Marina Abramova, Kristen R. Scott, Russell L. Dedrick
• Format: Article
• Language: English
• Published: Elsevier 2003-03-01
• Series: Neoplasia: An International Journal for Oncology Research
• Subjects: ING-1; ADCC; xenograft; pharmacokinetics; anti-Ep-CAM
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558603800064

ING-1(heMAb), a Human Engineered™ monoclonal antibody to epithelial cell adhesion molecule (Ep-CAM ), was evaluated for its in vitro and in vivo activity. The dissociation constant of ING-1(heMAb) for binding to Ep-CAM on HT-29 human colon tumor cells was 2 to 5 nM, similar to chimeric ING-1. In antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity assays, ING-1(heMAb) caused a concentration-dependent lysis of BT-20 breast, MCF-7 breast, HT-29 colon, CACO-2 colon tumor cells, with maximum cytolysis at approximately 1 μg/ml. After an intravenous injection in rats, plasma ING-1(heMAb) levels declined with an alpha half-life of 8 to 11 hours, a beta half-life of 20 days, typical of an IgG in a species without the target for ING-1. In nude mice with human HT-29 colon tumors, plasma ING-1(heMAb) levels declined more rapidly than in non-tumor-bearing mice, suggesting an enhanced clearance via the tumor-associated human Ep-CAM. In nude mice, intravenous treatments with ING-1(heMAb) twice a week for 3 weeks significantly suppressed the growth of human HT-29 colon and PC-3 prostate tumors in a dose-dependent manner, with 1.0 mg/kg providing the greatest benefit. These results indicate that Human Engineered™ ING-1(heMAb) is a high-affinity antibody with potent in vitro activity that targets and suppresses the growth of human tumors in vivo.