Pharmacodynamic and Antitumor Activity of BI 836880, a Dual Vascular Endothelial Growth Factor and Angiopoietin 2 Inhibitor, Alone and Combined with Programmed Cell Death Protein-1 Inhibition

Abstract

VEGF and angiopoietin-2 (ANG2) have complementary roles in angiogenesis and promote an immunosuppressive tumor microenvironment. It is anticipated that combination of VEGF and ANG2 blockade could provide superior activity to blockade of either pathway alone, and that addition of VEGF/ANG2 inhibition to an anti-programmed cell death protein-1 (PD-1) antibody could change the tumor microenvironment to support T-cell-mediated tumor cytotoxicity. Here, we describe the pharmacologic and antitumor activity of BI 836880, a humanized bispecific nanobody TM comprising two single variable domains blocking VEGF and ANG2, and an additional module for half-life extension in vivo. BI 836880 demonstrated high affinity and selectivity for human VEGF-A and ANG2, resulting in inhibition of downstream signaling of VEGF/ANG2 and a decrease in endothelial cell proliferation and survival. In vivo, BI 836880 exhibited significant antitumor activity in all patient-derived xenograft models tested, showing significantly greater tumor growth inhibition (TGI) than bevacizumab (VEGF inhibition) and AMG386 (ANG1/2 inhibition) in a range of models. In a Lewis lung carcinoma syngeneic tumor model, combination of PD-1 inhibition with VEGF inhibition showed superior efficacy versus blockade of either pathway alone. TGI was further increased with addition of ANG2 inhibition to VEGF/PD-1 blockade. VEGF/ANG2 inhibition had a strong anti-angiogenic effect. Our data suggest that blockade of VEGF and ANG2 with BI 836880 may offer improved antitumor activity versus blockade of either pathway alone and that combining VEGF/ANG2 inhibition with PD-1 blockade can further enhance antitumor effects. Significance statement (51/80 words)VEGF and ANG2 play key roles in angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Here, we show that BI 836880, a bispecific nanobody TM targeting VEGF and ANG2, demonstrates substantial antitumor activity in preclinical models.Combining VEGF/ANG2 inhibition with blockade of the PD-1 pathway can further improve antitumor activity.

Editorial: Tumor and immune cell interactions in the formation of organ-specific metastasis

“…They highlighted five factors, which facilitated lymphatic metastasis: Immunosuppression, PMN formation, lymphangiogenesis, epithelialto-mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling. Of note, compounds targeting angiopoietins to affect lymphangiogenesis (8) in cancer have been tested in combination with ICI for example in NSCLC (9). Finally, Li et al aim for deciphering the responsible mechanisms in cervical cancer lymphatic metastasis in order to implement this finding into clinical applications.…”