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.
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.
Amann
Maria
M
Micromet AG, Munich, Germany.
D'Argouges
Sandrine
S
Lorenczewski
Grit
G
Brischwein
Klaus
K
Kischel
Roman
R
Lutterbuese
Ralf
R
Mangold
Susanne
S
Rau
Doris
D
Volkland
Jörg
J
Pflanz
Stefan
S
Raum
Tobias
T
Münz
Markus
M
Kufer
Peter
P
Schlereth
Bernd
B
Baeuerle
Patrick A
PA
Friedrich
Matthias
M
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
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D016207:Cytokines; D000071858:Epithelial Cell Adhesion Molecule; D007155:Immunologic Factors