RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 331
OP 342
DO 10.1124/jpet.122.001255
VO 384
IS 3
A1 Irmgard Hofmann
A1 Anke Baum
A1 Marco H. Hofmann
A1 Francesca Trapani
A1 Claudia Reichel-Voda
A1 Diane Ehrensperger
A1 Martin Aichinger
A1 Florian Ebner
A1 Nicole Budano
A1 Norbert Schweifer
A1 Martina Sykora
A1 Erik Depla
A1 Joachim Boucneau
A1 Andreas Gschwind
A1 Norbert Kraut
A1 Frank Hilberg
A1 Klaus-Peter Künkele
YR 2023
UL http://jpet.aspetjournals.org/content/384/3/331.abstract
AB 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.