MEDI3617, a human anti-angiopoietin 2 monoclonal antibody, inhibits angiogenesis and tumor growth in human tumor xenograft models.
Angiopoietin 2 (Ang2) is an important regulator of angiogenesis, blood vessel maturation and integrity of the vascular endothelium. The correlation between the dynamic expression of Ang2 in tumors with regions of high angiogenic activity and a poor prognosis in many tumor types makes Ang2 an ideal drug target. We have generated MEDI3617, a human anti-Ang2 monoclonal antibody that neutralizes Ang2 by preventing its binding to the Tie2 receptor in vitro, and inhibits angiogenesis and tumor growth in vivo. Treatment of mice with MEDI3617 resulted in inhibition of angiogenesis in several mouse models including: FGF2-induced angiogenesis in a basement extract plug model, tumor and retinal angiogenesis. In xenograft tumor models, treatment with MEDI3617 resulted in a reduction in tumor angiogenesis and an increase in tumor hypoxia. The administration of MEDI3617 as a single agent to mice bearing human tumor xenografts resulted in tumor growth inhibition against a broad spectrum of tumor types. Combining MEDI3617 with chemotherapy or bevacizumab resulted in a delay in tumor growth and no body weight loss was observed in the combination groups. These results, combined with pharmacodynamic studies, demonstrate that treatment of tumor-bearing mice with MEDI3617 significantly inhibited tumor growth as a single agent by blocking tumor angiogenesis. Together, these data show that MEDI3617 is a robust antiangiogenic agent and support the clinical evaluation and biomarker development of MEDI3617 in cancer patients.
Department of Oncology, MedImmune, Gaithersburg, MD 20878, USA. leowc@medimmune.com
Ching Ching
CC
Leow
Karen
K
Coffman
Ivan
I
Inigo
Shannon
S
Breen
Meggan
M
Czapiga
Serguei
S
Soukharev
Neill
N
Gingles
Norman
N
Peterson
Christine
C
Fazenbaker
Rob
R
Woods
Bahija
B
Jallal
Sally-Ann
SA
Ricketts
Theresa
T
Lavallee
Steve
S
Coats
Yong
Y
Chang
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D016319:Corrosion Casting; D004305:Dose-Response Relationship, Drug; D005260:Female; D005453:Fluorescence; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D015861:Retinal Neovascularization / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C573120:MEDI3617; D042787:Receptor, TIE-2; D017239:Paclitaxel