TY - JOUR T1 - 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 331 LP - 342 DO - 10.1124/jpet.122.001255 VL - 384 IS - 3 AU - Irmgard Hofmann AU - Anke Baum AU - Marco H. Hofmann AU - Francesca Trapani AU - Claudia Reichel-Voda AU - Diane Ehrensperger AU - Martin Aichinger AU - Florian Ebner AU - Nicole Budano AU - Norbert Schweifer AU - Martina Sykora AU - Erik Depla AU - Joachim Boucneau AU - Andreas Gschwind AU - Norbert Kraut AU - Frank Hilberg AU - Klaus-Peter Künkele Y1 - 2023/03/01 UR - http://jpet.aspetjournals.org/content/384/3/331.abstract N2 - Vascular endothelial growth factor (VEGF) and angiopoietin (ANG)-2 have complementary roles in angiogenesis and promote an immunosuppressive tumor microenvironment. It is anticipated that the combination of VEGF and ANG2 blockade could provide superior activity to the blockade of either pathway alone and that the 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 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 the 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, the combination of PD-1 inhibition with VEGF inhibition showed superior efficacy versus the blockade of either pathway alone. TGI was further increased with the addition of ANG2 inhibition to VEGF/PD-1 blockade. VEGF/ANG2 inhibition had a strong antiangiogenic effect. Our data suggest that the blockade of VEGF and ANG2 with BI 836880 may offer improved antitumor activity versus the blockade of either pathway alone and that combining VEGF/ANG2 inhibition with PD-1 blockade can further enhance antitumor effects.SIGNIFICANCE STATEMENT Vascular endothelial growth factor (VEGF) and angiopoietin (ANG)-2 play key roles in angiogenesis and have an immunosuppressive effect in the tumor microenvironment. This study shows that BI 836880, a bispecific nanobody targeting VEGF and ANG2, demonstrates substantial antitumor activity in preclinical models. Combining VEGF/ANG2 inhibition with the blockade of the PD-1 pathway can further improve antitumor activity. ER -