title: Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3.
abstract: 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.
authors.affiliation: Micromet AG, Munich, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Amann
authors.forename: Klaus
authors.initials: K
authors.lastname: Brischwein
authors.forename: Petra
authors.initials: P
authors.lastname: Lutterbuese
authors.forename: Larissa
authors.initials: L
authors.lastname: Parr
authors.forename: Laetitia
authors.initials: L
authors.lastname: Petersen
authors.forename: Grit
authors.initials: G
authors.lastname: Lorenczewski
authors.forename: Eva
authors.initials: E
authors.lastname: Krinner
authors.forename: Sandra
authors.initials: S
authors.lastname: Bruckmeier
authors.forename: Sandra
authors.initials: S
authors.lastname: Lippold
authors.forename: Roman
authors.initials: R
authors.lastname: Kischel
authors.forename: Ralf
authors.initials: R
authors.lastname: Lutterbuese
authors.forename: Peter
authors.initials: P
authors.lastname: Kufer
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Bernd
authors.initials: B
authors.lastname: Schlereth
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology; D017252:CD3 Complex / Q000032:analysis / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000276:immunology*; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D057127:Single-Chain Antibodies; D014018:Tissue Distribution
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; C509173:MT110 monoclonal antibody; D057127:Single-Chain Antibodies