A novel angiopoietin-2 selective fully human antibody with potent anti-tumoral and anti-angiogenic efficacy and superior side effect profile compared to Pan-Angiopoietin-1/-2 inhibitors

There is increasing experimental evidence for an important role of Angiopoietin-2 (Ang-2) in tumor angiogenesis and progression. In addition, Ang-2 is up-regulated in many cancer types and correlated with poor prognosis. To investigate the functional role of Ang-2 inhibition in tumor development and...

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Bibliographic Details
Published in:PloS one 2013-02, Vol.8 (2), p.e54923-e54923
Main Authors: Thomas, Markus, Kienast, Yvonne, Scheuer, Werner, Bähner, Monika, Kaluza, Klaus, Gassner, Christian, Herting, Frank, Brinkmann, Ulrich, Seeber, Stefan, Kavlie, Anita, Welschof, Martin, Ries, Stefan, Weidner, K Michael, Regula, Jörg T, Klein, Christian
Format: Article
Language:English
Subjects:
Angiogenesis
Angiopoietin
Angiopoietin-1 - antagonists & inhibitors
Angiopoietin-1 - immunology
Angiopoietin-2 - antagonists & inhibitors
Angiopoietin-2 - immunology
Animal models
Animals
Antiangiogenics
Antibodies
Antibodies, Neutralizing - immunology
Antibodies, Neutralizing - pharmacology
Antibody Specificity
Antineoplastic agents
Antineoplastic Agents - immunology
Antineoplastic Agents - pharmacology
Arthritis
Biology
Blood vessels
Breast cancer
Cancer
Cell Line, Tumor
Chemical compounds
Colonic Neoplasms - blood supply
Colonic Neoplasms - drug therapy
Colonic Neoplasms - immunology
Comparative analysis
Complications and side effects
Cornea - drug effects
Cornea - immunology
Female
HEK293 Cells
Humans
Immunoglobulins
Inhibition
Leukemia
Ligands
Lungs
Medicine
Metastasis
Mice
Mice, Inbred BALB C
Mice, SCID
Microvessels - drug effects
Microvessels - immunology
Neovascularization, Pathologic - drug therapy
Neovascularization, Pathologic - immunology
Oncology
Pharmacology
Phosphorylation
Physiological aspects
Physiology
Random Allocation
Receptor, TIE-2 - antagonists & inhibitors
Receptor, TIE-2 - immunology
Selectivity
Smooth muscle
Trachea
Tumor cells
Tumors
Xenograft Model Antitumor Assays
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Description
Summary:There is increasing experimental evidence for an important role of Angiopoietin-2 (Ang-2) in tumor angiogenesis and progression. In addition, Ang-2 is up-regulated in many cancer types and correlated with poor prognosis. To investigate the functional role of Ang-2 inhibition in tumor development and progression, we generated novel fully human antibodies that neutralize specifically the binding of Ang-2 to its receptor Tie2. The selected antibodies LC06 and LC08 recognize both rodent and human Ang-2 with high affinity, but LC06 shows a higher selectivity for Ang-2 over Ang-1 compared to LC08 which can be considered an Ang-2/Ang-1 cross-reactive antibody. Our data demonstrate that Ang-2 blockade results in potent tumor growth inhibition and pronounced tumor necrosis in subcutaneous and orthotopic tumor models. These effects are attended with a reduction of intratumoral microvessel density and tumor vessels characterized by fewer branches and increased pericyte coverage. Furthermore, anti-Ang-2 treatment strongly inhibits the dissemination of tumor cells to the lungs. Interestingly, in contrast to the Ang-2/Ang-1 cross-reactive antibody LC08 that leads to a regression of physiological vessels in the mouse trachea, the inhibition with the selective anti-Ang-2 antibody LC06 appears to be largely restricted to tumor vasculature without obvious effects on normal vasculature. Taken together, these data provide strong evidence for the selective Ang-2 antibody LC06 as promising new therapeutic agent for the treatment of various cancers.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0054923