title: Anti-tumoral, anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2.
abstract: Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody (Ang-2-VEGF-TAvi6) targeting VEGF-A with 2 arms based on bevacizumab (Avastin®), and targeting Ang-2 with 2 arms based on a novel anti-Ang-2 antibody (LC06). The two Ang-2-targeting single-chain variable fragments are disulfide-stabilized and fused to the C-terminus of the heavy chain of bevacizumab. Treatment with Ang-2-VEGF-A-TAvi6 led to a complete abrogation of angiogenesis in the cornea micropocket assay. Metastatic spread and tumor growth of subcutaneous, orthotopic and anti-VEGF-A resistant tumors were also efficiently inhibited. These data further establish Ang-2-VEGF bispecific antibodies as a promising anti-angiogenic, anti-metastatic and anti-tumor agent for the treatment of cancer.
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Werner
authors: W
authors: Scheuer
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Markus
authors: M
authors: Thomas
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Petra
authors: P
authors: Hanke
authors: b Roche Innovation Center Zurich, Roche Pharma Research and Early Development , Wagistrasse 18, Schlieren , Switzerland.
authors: Johannes
authors: J
authors: Sam
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Franz
authors: F
authors: Osl
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Diana
authors: D
authors: Weininger
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Monika
authors: M
authors: Baehner
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Stefan
authors: S
authors: Seeber
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Hubert
authors: H
authors: Kettenberger
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Jürgen
authors: J
authors: Schanzer
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Ulrich
authors: U
authors: Brinkmann
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: K Michael
authors: KM
authors: Weidner
authors: a Roche Innovation Center Penzberg, Roche Pharma Research and Early Development , Nonnenwald 2, Penzberg , Germany.
authors: Jörg
authors: J
authors: Regula
authors: b Roche Innovation Center Zurich, Roche Pharma Research and Early Development , Wagistrasse 18, Schlieren , Switzerland.
authors: Christian
authors: C
authors: Klein
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors*; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Angiopoietin-2; bispecific; BsAb; scFv; VEGF-A