title: Antitumor activity of an EpCAM/CD3-bispecific BiTE antibody during long-term treatment of mice in the absence of T-cell anergy and sustained cytokine release.
abstract: muS110 is a BiTE antibody bispecific for murine EpCAM (CD326) and murine CD3. MT110, its human-specific analog, is in a clinical phase 1 trial for treatment of patients with adenocarcinoma of the lung or gastrointestinal tract. Recent studies have shown a therapeutic window for muS110, have explored single-dose toxicity of muS110, and have found that a 1-week low-dose treatment dramatically increased the tolerability of mice to very high doses of muS110 (Cancer Immunol. Immunother. 2009;58:95-109). Here we analyzed the impact of long-term, high-dose treatment of mice with muS110 on antitumor activity and functionality of T cells. After an initial self-limiting cytokine release, the 1-week adaptation period effectively blunted further cytokine production in response to a subsequent high-dose treatment with muS110. The much-increased tolerability of mice adapted to muS110 was not because of anergy of T cells. T cells isolated from chronically muS110-treated mice fully retained their cytotoxic potential, proliferative capacity, and responsiveness to stimulation by either muS110 or anti-CD3/anti-CD28/interleukin-2 when compared with T cells from control mice. Unimpaired T-cell performance was also evident from the effective prevention of orthotopic 4T1 breast tumor outgrowth in mice treated long term with escalating doses of muS110. Finally, we show that muS110 and MT110 recognize orthologous epitopes on mouse and human EpCAM proteins, suggesting that the target-related safety profile of muS110 in mice may be predictive for MT110 in humans.
authors.affiliation: Micromet AG, Munich, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Amann
authors.forename: Sandrine
authors.initials: S
authors.lastname: D'Argouges
authors.forename: Grit
authors.initials: G
authors.lastname: Lorenczewski
authors.forename: Klaus
authors.initials: K
authors.lastname: Brischwein
authors.forename: Roman
authors.initials: R
authors.lastname: Kischel
authors.forename: Ralf
authors.initials: R
authors.lastname: Lutterbuese
authors.forename: Susanne
authors.initials: S
authors.lastname: Mangold
authors.forename: Doris
authors.initials: D
authors.lastname: Rau
authors.forename: Jörg
authors.initials: J
authors.lastname: Volkland
authors.forename: Stefan
authors.initials: S
authors.lastname: Pflanz
authors.forename: Tobias
authors.initials: T
authors.lastname: Raum
authors.forename: Markus
authors.initials: M
authors.lastname: Münz
authors.forename: Peter
authors.initials: P
authors.lastname: Kufer
authors.forename: Bernd
authors.initials: B
authors.lastname: Schlereth
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D017635:Clonal Anergy / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D015202:Protein Engineering; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D016207:Cytokines; D000071858:Epithelial Cell Adhesion Molecule; D007155:Immunologic Factors