Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3.
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.
Amann
Maria
M
Micromet AG, Munich, Germany.
Brischwein
Klaus
K
Lutterbuese
Petra
P
Parr
Larissa
L
Petersen
Laetitia
L
Lorenczewski
Grit
G
Krinner
Eva
E
Bruckmeier
Sandra
S
Lippold
Sandra
S
Kischel
Roman
R
Lutterbuese
Ralf
R
Kufer
Peter
P
Baeuerle
Patrick A
PA
Schlereth
Bernd
B
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
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