title: 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.
abstract: 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.
authors: Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany. markus.thomas@roche.com
authors: Markus
authors: M
authors: Thomas
authors: Yvonne
authors: Y
authors: Kienast
authors: Werner
authors: W
authors: Scheuer
authors: Monika
authors: M
authors: Bähner
authors: Klaus
authors: K
authors: Kaluza
authors: Christian
authors: C
authors: Gassner
authors: Frank
authors: F
authors: Herting
authors: Ulrich
authors: U
authors: Brinkmann
authors: Stefan
authors: S
authors: Seeber
authors: Anita
authors: A
authors: Kavlie
authors: Martin
authors: M
authors: Welschof
authors: Stefan
authors: S
authors: Ries
authors: K Michael
authors: KM
authors: Weidner
authors: Jörg T
authors: JT
authors: Regula
authors: Christian
authors: C
authors: Klein
mesh_terms: D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000276:immunology; D003315:Cornea / Q000187:drug effects / Q000276:immunology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D055806:Microvessels / Q000187:drug effects / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000276:immunology; D010766:Phosphorylation; D011897:Random Allocation; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D042787:Receptor, TIE-2
references: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11205-10
references: 12163646
references: Chest. 2007 Jul;132(1):200-6
references: 17505039
references: Cardiovasc Res. 2001 Feb 16;49(3):659-70
references: 11166279
references: Int J Oncol. 2012 May;40(5):1321-30
references: 22327175
references: Oncogene. 2000 Sep 14;19(39):4549-52
references: 11002428
references: J Cell Sci. 2002 Jan 1;115(Pt 1):175-83
references: 11801735
references: Clin Cancer Res. 2009 Feb 15;15(4):1384-92
references: 19228739
references: Blood. 2004 Jun 1;103(11):4150-6
references: 14976056
references: Microcirculation. 2011 Oct;18(7):598-607
references: 21851472
references: Cancer Res. 2007 May 1;67(9):4254-63
references: 17483337
references: Cancer Cell. 2011 Apr 12;19(4):512-26
references: 21481792
references: Cancer Cell. 2009 Mar 3;15(3):232-9
references: 19249681
references: Cancer Res. 2003 Jun 15;63(12):3370-7
references: 12810673
references: Science. 1997 Jul 4;277(5322):55-60
references: 9204896
references: Curr Pharm Des. 2007;13(27):2795-809
references: 17897024
references: Clin Exp Metastasis. 2002;19(7):571-82
references: 12498386
references: Gynecol Oncol. 2012 Jan;124(1):5-9
references: 22153126
references: Cell. 1996 Dec 27;87(7):1171-80
references: 8980224
references: Cancer. 2012 Dec 15;118(24):6152-61
references: 22692704
references: Mol Cancer Ther. 2010 Oct;9(10):2641-51
references: 20937592
references: J Clin Oncol. 2012 Feb 1;30(4):362-71
references: 22184370
references: J Cell Sci. 2012 May 1;125(Pt 9):2212-23
references: 22357955
references: Exp Neurol. 1999 Oct;159(2):391-400
references: 10506510
references: Leukemia. 2008 Feb;22(2):287-93
references: 17943167
references: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8904-9
references: 12861074
references: Breast Cancer Res Treat. 2006 Aug;98(3):261-6
references: 16538528
references: Cancer Cell. 2012 Jan 17;21(1):66-81
references: 22264789
references: J Leukoc Biol. 2006 Oct;80(4):719-26
references: 16864601
references: Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11187-92
references: 21690412
references: Cancer Cell. 2004 Nov;6(5):507-16
references: 15542434
references: Cancer Res. 2003 Jun 15;63(12):3403-12
references: 12810677
references: Am J Pathol. 1998 Nov;153(5):1459-66
references: 9811337
references: Cancer Cell. 2009 Mar 3;15(3):220-31
references: 19249680
references: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15491-6
references: 17030814
references: Anticancer Res. 2000 Nov-Dec;20(6D):5217-20
references: 11326698
references: Circ Res. 1997 Oct;81(4):567-74
references: 9314838
references: Graefes Arch Clin Exp Ophthalmol. 2001 Dec;239(12):972-5
references: 11820705
references: Clin Cancer Res. 2010 Jun 1;16(11):3044-56
references: 20501621
references: Nat Cell Biol. 2008 May;10(5):527-37
references: 18425119
references: J Biol Chem. 2003 Jan 17;278(3):1721-7
references: 12427764
references: Development. 1998 May;125(9):1591-8
references: 9521897
references: Cancer. 2001 Sep 1;92(5):1138-43
references: 11571726
references: Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77
references: 19234476
references: Cancer Res. 2009 Feb 15;69(4):1324-33
references: 19208839
references: EMBO J. 2008 Feb 6;27(3):522-34
references: 18200044
references: Mol Cancer Ther. 2010 Jan;9(1):145-56
references: 20053776
references: Am J Pathol. 2009 Nov;175(5):2159-70
references: 19815705
references: Science. 1999 Dec 24;286(5449):2511-4
references: 10617467
references: Science. 1999 Jun 18;284(5422):1994-8
references: 10373119
references: Cell. 1996 Dec 27;87(7):1161-9
references: 8980223
references: J Surg Res. 2008 May 1;146(1):16-23
references: 17950331
references: Clin Cancer Res. 2011 Mar 1;17(5):1001-11
references: 21233403
references: J Clin Oncol. 2009 Jul 20;27(21):3557-65
references: 19546406
references: Br J Cancer. 1999 Feb;79(5-6):707-17
references: 10070858
references: Cancer Res. 2006 Apr 1;66(7):3639-48
references: 16585189