Context-Dependent Role of Angiopoietin-1 Inhibition in the Suppression of Angiogenesis and Tumor Growth: Implications for AMG 386, an Angiopoietin-1/2–Neutralizing Peptibody

Abstract

AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings. Mol Cancer Ther; 9(10); 2641–51.

Antagonism of Ang-Tie2 and Dll4-Notch signaling has opposing effects on tumor endothelial cell proliferation, evidenced by a new flow cytometry method

“…[4][5][6] Recently, we reported selective inhibition of Ang-2 (but not Ang-1) was responsible for blocking both TAEC proliferation in tumor xenografts and VEGF-mediated rat corneal angiogenesis. 7,11 Our current study highlights that dual inhibition of Ang-1 and Ang-2 Tumor-associated endothelial cell proliferation M Payton et al VEGF) would reduce the basal rate of TAEC proliferation, thus permitting more complete suppression of BrdUrd uptake by trebananib. In contrast to blocking angiopoietin signaling with trebananib, antagonism of Dll4 signaling with an anti-Dll4 antibody induced rapid (within 24 h) hyperproliferation of TAECs in U-87-GFP tumor xenografts.…”

“…Treatment with trebananib at lower doses (6 mg/kg) also inhibits TAEC proliferation in the COLO 205 tumor xenograft model. 11 To characterize the effects of inhibiting angiopoietin-Tie2 or Dll4-Notch signaling in a highly vascularized tumor model, mice with established U-87-GFP tumors were treated with a single injection of either trebananib (5.6 mg/kg, s.c.) or anti-Dll4 mouse monoclonal antibody (12 mg/kg, i.p.). U-87-GFP tumors were collected from mice treated with either anti-Dll4 antibody or trebananib at either 24 h (antiDll4 antibody) or 48 h (trebananib) along with time-matched vehicle-treated controls.…”

“…5,6 Trebananib (AMG 386), an investigational peptide-Fc fusion protein that prevents binding of angiopoietins 1 and 2 (ang-1 and ang-2) to their receptor Tie2, inhibits angiogenesis, growth of tumor xenografts, and proliferation of tumor endothelial cells. [7][8][9][10][11][12] In contrast, several studies have shown that administration of an anti-Dll4-specific antibody stimulates the proliferation of endothelial tip cells and increases vascular density in human tumor xenografts. [13][14][15][16][17] However, this is believed to contribute to tumor starvation and suppression of tumor growth as inhibition of Dll4-Notch signaling results in the formation of nonfunctional immature vessels leading to poor tumor perfusion.…”

Current and Emerging Therapies for the Management of Diabetic Retinopathy

“…Growth factors which contribute DR development includes basic fibrobroblast growth factor (bFGF) (Armstrong et al, 1998), insulin-like growth factor-1 (IGF-1) (Hueber et al, 1996;Haurigot et al, 2009), angiopoietin-1 and -2 (Patel et al, 2005;Rangasamy et al, 2011), stromal-derived factor-1 (Coxon et al, 2010), epidermal growth factor (EGF) (Lev-Ran et al, 1990), transforming growth factor-beta 2 (TGF-2) (Min et al, 2006), platelet-derived growth factors (PDGFs) (Praidou et al, 2009), and erythropoietin (Eckardt, 2009). Among these growth factors VEGF plays an important role in DR pathogenesis.…”

Emerging techniques to treat corneal neovascularisation

“…53 In the cornea, inhibition of angiopoietin-2 suppressed angiogenesis; however, additional inhibition of angiopoietin-1 yielded no further suppression of angiogenesis. 54 …”