ABL001, a Bispecific Antibody Targeting VEGF and DLL4, with Chemotherapy, Synergistically Inhibits Tumor Progression in Xenograft Models.

Dong-Hoon Yeom,Weon-Kyoo You,Yo-Seob Lee,Dongin Kim,Sang Hoon Lee,Sunju Lee,Yong-Soo Choi,Eunsin Ha,Han-Byul Lee,Jin-Hyung Ahn,Byungje Sung,Ilhwan Ryu

doi:10.3390/ijms22010241

Dong-Hoon Yeom, Weon-Kyoo You + Show 10 more

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https://doi.org/10.3390/ijms22010241

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Abstract

Delta-like-ligand 4 (DLL4) is a promising target to augment the effects of VEGF inhibitors. A simultaneous blockade of VEGF/VEGFR and DLL4/Notch signaling pathways leads to more potent anti-cancer effects by synergistic anti-angiogenic mechanisms in xenograft models. A bispecific antibody targeting VEGF and DLL4 (ABL001/NOV1501/TR009) demonstrates more potent in vitro and in vivo biological activity compared to VEGF or DLL4 targeting monoclonal antibodies alone and is currently being evaluated in a phase 1 clinical study of heavy chemotherapy or targeted therapy pre-treated cancer patients (ClinicalTrials.gov Identifier: NCT03292783). However, the effects of a combination of ABL001 and chemotherapy on tumor vessels and tumors are not known. Hence, the effects of ABL001, with or without paclitaxel and irinotecan were evaluated in human gastric or colon cancer xenograft models. The combination treatment synergistically inhibited tumor progression compared to each monotherapy. More tumor vessel regression and apoptotic tumor cell induction were observed in tumors treated with the combination therapy, which might be due to tumor vessel normalization. Overall, these findings suggest that the combination therapy of ABL001 with paclitaxel or irinotecan would be a better clinical strategy for the treatment of cancer patients.

Highlights

Published: 29 December 2020Tumor angiogenesis, the formation of new blood vessels in solid tumors, plays an important role in tumor cell survival, growth, and metastasis [1]
vascular endothelial growth factor (VEGF)/VEGFR blockade can inhibit VEGF-driven tumor angiogenesis, and the regression of tumor vessels is dependent on the VEGF signaling pathway
To confirm the effects of ABL001 on tumor progression and to select the appropriate xenograft models for testing a combination treatment of ABL001 with chemotherapy, we evaluated the anti-cancer effects of ABL001 using several human gastric cancer (NUGC-3, MKN45, and SNU16 for mouse version of ABL001 bispecific antibody (mABL001), and GAPF006 for ABL001) xenograft models (Figure 1A), and human colon cancer (Colo205, WiDr, SW48, and SW620 for mABL001)

Summary

Introduction

The formation of new blood vessels in solid tumors, plays an important role in tumor cell survival, growth, and metastasis [1]. A major driving force of tumor angiogenesis is the signaling pathway involving vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) [2]. Several angiogenesis inhibitors, including antibodies and small molecule compounds targeting the VEGF/VEGFR signaling pathway, have been approved by the Food and Drug Administration (FDA), and used for the treatment of many different types of cancers [3]. VEGF/VEGFR inhibitors, including antibody fragments, aptamers, and VEGF-Traps were approved and used for the treatment of ocular diseases caused by pathological angiogenesis [4,5,6,7,8]. VEGF inhibitors alone are not capable of destroying all tumor blood vessels. Some cancer patients are eventually refractory to anti-VEGF therapy, Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations

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