Anti-transforming growth factor beta receptor II antibody has therapeutic efficacy against primary tumor growth and metastasis through multieffects on cancer, stroma, and immune cells.
OBJECTIVE
Transforming growth factor beta (TGFbeta) is a pleiotropic cytokine that affects tumor growth, metastasis, stroma, and immune response. We investigated the therapeutic efficacy of anti-TGFbeta receptor II (TGFbeta RII) antibody in controlling metastasis and tumor growth as well as enhancing antitumor immunity in preclinical tumor models.


METHODS
We generated neutralizing antibodies to TGFbeta RII and assessed the antibody effects on cancer, stroma, and immune cells in vitro. The efficacy and mechanism of action of the antibody as monotherapy and in combination with chemotherapy in suppression of primary tumor growth and metastasis were evaluated in several tumor models.


RESULTS
Anti-TGFbeta RII antibody blocked TGFbeta RII binding to TGFbeta 1, 2, and 3, and attenuated the TGFbeta-mediated activation of downstream Smad2 kinase, invasion of cancer cells, motility of endothelial and fibroblast cells, and induction of immunosuppressive cells. Treatment with the antibody significantly suppressed primary tumor growth and metastasis and enhanced natural killer and CTL activity in tumor-bearing mice. Immunohistochemistry analysis showed cancer cell apoptosis and massive necrosis, and increased tumor-infiltrating T effector cells and decreased tumor-infiltrating Gr-1+ myeloid cells in the antibody-treated tumors. Fluorescence-activated cell sorting analysis indicated the significant reduction of peripheral Gr-1+/CD11b+ myeloid cells in treated animals. Concomitant treatment with the cytotoxic agent cyclophosphamide resulted in a significantly increased antitumor efficacy against primary tumor growth and metastasis.


CONCLUSIONS
These preclinical data provide a foundation to support using anti-TGFbeta RII antibody as a therapeutic agent for TGFbeta RII-dependent cancer with metastatic capacity.
Department of Antibody Technology & Immunology, Clinical Research, and Research, ImClone Systems, New York, New York 10014, USA.
Zhaojing
Z
Zhong
Kyla Driscoll
KD
Carroll
Desiree
D
Policarpio
Carla
C
Osborn
Michael
M
Gregory
Rajiv
R
Bassi
Xenia
X
Jimenez
Marie
M
Prewett
Gregory
G
Liebisch
Kris
K
Persaud
Douglas
D
Burtrum
Su
S
Wang
David
D
Surguladze
Stanley
S
Ng
Heather
H
Griffith
Paul
P
Balderes
Jacqueline
J
Doody
Jonathan D
JD
Schwartz
Hagop
H
Youssoufian
Eric K
EK
Rowinsky
Dale L
DL
Ludwig
Larry
L
Witte
Zhenping
Z
Zhu
Yan
Y
Wu
D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology*; D051899:Smad2 Protein / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II