Therapeutic Window of MuS110, a Single-Chain Antibody Construct Bispecific for Murine EpCAM and Murine CD3

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008, Vol.68 (1), p.143-151
• Main Authors: AMANN, Maria, BRISCHWEIN, Klaus, LUTTERBUESE, Ralf, KUFER, Peter, BAEUERLE, Patrick A, SCHLERETH, Bernd, LUTTERBUESE, Petra, PARR, Larissa, PETERSEN, Laetitia, LORENCZEWSKI, Grit, KRINNER, Eva, BRUCKMEIER, Sandra, LIPPOLD, Sandra, KISCHEL, Roman
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bispecific - immunology; Antibodies, Bispecific - pharmacokinetics; Antibodies, Bispecific - therapeutic use; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antigens, Neoplasm - analysis; Antigens, Neoplasm - immunology; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - immunology; CD3 Complex - analysis; CD3 Complex - immunology; Cell Adhesion Molecules - analysis; Cell Adhesion Molecules - immunology; Cricetinae; Cytotoxicity, Immunologic; Epithelial Cell Adhesion Molecule; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Medical sciences; Mice; Neoplasms - drug therapy; Neoplasms - immunology; Pharmacology. Drug treatments; Single-Chain Antibodies; Tissue Distribution; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-2182

EpCAM (CD326) is one of the most frequently and highly expressed tumor-associated antigens known and recently has also been found on cancer stem cells derived from human breast, colon, prostate, and pancreas tumors. However, like many other tumor-associated antigens used for antibody-based immunotherapeutic approaches, EpCAM is expressed on normal tissues including epithelia of pancreas, colon, lung, bile ducts, and breast. To assess the therapeutic window of an EpCAM/CD3-bispecific single-chain antibody construct of the bispecific T-cell engager (BiTE) class, we constructed murine surrogate of MT110 (muS110) from single-chain antibodies specific for murine EpCAM and CD3 antigens. Immunhistochemical analysis showed that, with minor differences, the expression of EpCAM protein on a large variety of tissues from man and mouse was similar with respect to distribution and level. MuS110 exhibited significant antitumor activity at as low as 5 microg/kg in both syngeneic 4T1 orthotopic breast cancer and CT-26 lung cancer mouse models. Dosing of muS110 for several weeks up to 400 microg/kg by intraanimal dose escalation was still tolerated, indicating existence of a significant therapeutic window for an EpCAM-specific BiTE antibody in mice. MuS110 was found to have similar in vitro characteristics and in vivo antitumor activity as MT110, a human EpCAM/human CD3-bispecific BiTE antibody that currently is in formal preclinical development.