Synergistic antitumor activity of a DLL4/VEGF bispecific therapeutic antibody in combination with irinotecan in gastric cancer

Abstract

Notch signaling has been identified as a critical pathway in gastric cancer (GC) progression and metastasis, and inhibition of Delta-like ligand 4 (DLL4), a Notch ligand, is suggested as a potent therapeutic approach for GC. Expression of both DLL4 and vascular endothelial growth factor receptor 2 (VEGFR2) was similar in the malignant tissues of GC patients. We focused on vascular endothelial growth factor (VEGF), a known angiogenesis regulator and activator of DLL4. Here, we used ABL001, a DLL4/VEGF bispecific therapeutic antibody, and investigated its therapeutic effect in GC. Treatment with human DLL4 therapeutic antibody (anti-hDLL4) or ABL001 slightly reduced GC cell growth in monolayer culture; however, they significantly inhibited cell growth in 3D-culture, suggesting a reduction in the cancer stem cell population. Treatment with anti-hDLL4 or ABL001 also decreased GC cell migration and invasion. Moreover, the combined treatment of irinotecan with anti-hDLL4 or ABL001 showed synergistic antitumor activity. Both combination treatments further reduced cell growth in 3D-culture as well as cell invasion. Interestingly, the combination treatment of ABL001 with irinotecan synergistically reduced the GC burden in both xenograft and orthotopic mouse models. Collectively, DLL4 inhibition significantly decreased cell motility and stem-like phenotype and the combination treatment of DLL4/VEGF bispecific therapeutic antibody with irinotecan synergistically reduced the GC burden in mouse models. Our data suggest that ABL001 potentially represents a potent agent in GC therapy. Further biochemical and pre-clinical studies are needed for its application in the clinic.

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

“…The combination treatment of ABL001 with paclitaxel or irinotecan demonstrated more potent inhibition of tumor progression in these xenograft models, which is consistent with the previous report of the study collaborator [ 24 ]. Such potent anti-cancer effects of the combination therapy might be related to more significantly regressed tumor blood vessels, as compared to monotherapy with ABL001 or chemotherapy alone.…”

“…ABL001 (NOV1501/TR009), a bispecific antibody targeting VEGF and DLL4, is being developed as an anti-angiogenic cancer therapeutic that strengthens the effects of VEGF inhibitors and eventually overcomes resistance to anti-VEGF therapy [ 16 , 19 , 20 , 23 ]. ABL001 demonstrated more potent anti-angiogenic and anti-cancer effects in vitro and in vivo, as compared to the VEGF-targeting or the DLL4-targeting monoclonal antibodies alone, in various assay systems [ 23 , 24 ]. Based on the overall results of preclinical studies, the safety and tolerability of ABL001 are currently being tested with cancer patients previously treated heavily with chemotherapy or targeted therapy [ 25 ].…”

“…ABL001 is a bispecific antibody that simultaneously targets both DLL4 and VEGF, by linking each C-terminal of an anti-VEGF antibody (bevacizumab-similar) with a DLL4-binding single-chain Fv (scFv) [ 22 , 23 ]. In previous studies, ABL001 has demonstrated anti-cancer effects with higher potency in several human cancer xenograft models compared to that shown by the VEGF-targeting antibody (bevacizumab-similar) and the DLL4-targeting monoclonal antibody alone [ 23 , 24 ].…”

The role of Notch ligand, Delta-like ligand 4 (DLL4), in cancer angiogenesis—implications for therapy

“…Thus, VEGF activates angiogenesis and Notch signalling helps VEGF do this. A reasonable solution would be to introduce combined DLL4 and VEGF in cancer therapy [37]. Some studies revealed that DLL4 itself contributes to tumour growth through bevacizumab, a VEGF inhibitor.…”

“…A great number of blocking agents of DLL4/Notch signalling, including anti-DLL4 antibodies, DNA vaccination, soluble DLL4-Fc, Notch Fc decoys, Notch antibodies and gamma-secretase inhibitors have been studied in preclinical tumour models [36][37][38][39][40][41][42][43]. As mentioned above, one of these approaches is connected to specific targeting of DLL4 by the use of anti-DLL4 antibodies.…”