title: A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models.
abstract: Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.3) was developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms of reduced immunogenicity and increased half-life to block Ang2 function. The 3.19.3 antibody potently binds Ang2 with an equilibrium dissociation constant of 86 pmol/L, leading to inhibition of Tie2 receptor phosphorylation in cell-based assays. In preclinical models, 3.19.3 treatment blocked blood vessel formation in Matrigel plug assays and in human tumor xenografts. In vivo studies with 3.19.3 consistently showed broad antitumor activity as a single agent across a panel of diverse subcutaneous and orthotopic xenograft models. Combination studies of 3.19.3 with cytotoxic drugs or anti-vascular endothelial growth factor agents showed significant improvements in antitumor activity over single-agent treatments alone with no apparent evidence of increased toxicity. Initial pharmacokinetic profiling studies in mice and nonhuman primates suggested that 3.19.3 has a predicted human half-life of 10 to 14 days. These studies provide preclinical data for 3.19.3 as a potential new antiangiogenic therapy as a single agent or in combination with chemotherapy or vascular endothelial growth factor inhibitors for the treatment of cancer.
authors.affiliation: AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA. jeff.brown@astrazeneca.com
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brown
authors.forename: Z Alexander
authors.initials: ZA
authors.lastname: Cao
authors.forename: Maria
authors.initials: M
authors.lastname: Pinzon-Ortiz
authors.forename: Jane
authors.initials: J
authors.lastname: Kendrew
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.forename: Shenghua
authors.initials: S
authors.lastname: Wen
authors.forename: Joe Q
authors.initials: JQ
authors.lastname: Zhou
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tabrizi
authors.forename: Steve
authors.initials: S
authors.lastname: Emery
authors.forename: Brenda
authors.initials: B
authors.lastname: McDermott
authors.forename: Lourdes
authors.initials: L
authors.lastname: Pablo
authors.forename: Patricia
authors.initials: P
authors.lastname: McCoon
authors.forename: Vahe
authors.initials: V
authors.lastname: Bedian
authors.forename: David C
authors.initials: DC
authors.lastname: Blakey
mesh_terms: D042702:Angiopoietin-2 / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000918:Antibody Specificity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D006801:Humans; D007797:Laminin / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D011323:Primates; D011485:Protein Binding / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D042702:Angiopoietin-2; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042442:Vascular Endothelial Growth Factors; C059485:matrigel; D003094:Collagen; D042787:Receptor, TIE-2