title: Simultaneous blockade of VEGF and Dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis.
abstract: Several angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway have been approved for cancer treatment. However, VEGF inhibitors alone were shown to promote tumor invasion and metastasis by increasing intratumoral hypoxia in some preclinical and clinical studies. Emerging reports suggest that Delta-like ligand 4 (Dll4) is a promising target of angiogenesis inhibition to augment the effects of VEGF inhibitors. To evaluate the effects of simultaneous blockade against VEGF and Dll4, we developed a bispecific antibody, HD105, targeting VEGF and Dll4. The HD105 bispecific antibody, which is composed of an anti-VEGF antibody (bevacizumab-similar) backbone C-terminally linked with a Dll4-targeting single-chain variable fragment, showed potent binding affinities against VEGF (KD: 1.3 nM) and Dll4 (KD: 30 nM). In addition, the HD105 bispecific antibody competitively inhibited the binding of ligands to their receptors, i.e., VEGF to VEGFR2 (EC50: 2.84 ± 0.41 nM) and Dll4 to Notch1 (EC50: 1.14 ± 0.06 nM). Using in vitro cell-based assays, we found that HD105 effectively blocked both the VEGF/VEGFR2 and Dll4/Notch1 signaling pathways in endothelial cells, resulting in a conspicuous inhibition of endothelial cell proliferation and sprouting. HD105 also suppressed Dll4-induced Notch1-dependent activation of the luciferase gene. In vivo xenograft studies demonstrated that HD105 more efficiently inhibited the tumor progression of human A549 lung and SCH gastric cancers than an anti-VEGF antibody or anti-Dll4 antibody alone. In conclusion, HD105 may be a novel therapeutic bispecific antibody for cancer treatment.
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Dongheon
authors.initials: D
authors.lastname: Lee
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Dongin
authors.initials: D
authors.lastname: Kim
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Yu Bin
authors.initials: YB
authors.lastname: Choi
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Kyungjae
authors.initials: K
authors.lastname: Kang
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Eun-Sil
authors.initials: ES
authors.lastname: Sung
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Jin-Hyung
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Junseo
authors.initials: J
authors.lastname: Goo
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Yeom
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Jang
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Kyung Duk
authors.initials: KD
authors.lastname: Moon
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: a Hanwha Chemical R&D Center , Biologics Business Unit , Gajeong-Ro, Yuseong-Gu , Daejeon , Republic of Korea.
authors.forename: Weon-Kyoo
authors.initials: WK
authors.lastname: You
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Anti-angiogenesis; VEGF; anti-cancer; biologics; delta-like ligand; therapeutic antibody