title: Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment.
abstract: A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors.
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
authors.forename: Il-Kug
authors.initials: IK
authors.lastname: Kim
authors.affiliation: Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea; Samsung Advanced Institute of Technology, Suwon 16678, Republic of Korea.
authors.forename: Sangyeul
authors.initials: S
authors.lastname: Han
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.
authors.forename: Intae
authors.initials: I
authors.lastname: Park
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
authors.forename: Chan
authors.initials: C
authors.lastname: Kim
authors.affiliation: Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.
authors.forename: Jeomil
authors.initials: J
authors.lastname: Bae
authors.affiliation: Samsung Advanced Institute of Technology, Suwon 16678, Republic of Korea.
authors.forename: Seung Ja
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Department of Neurosurgery, Asan Medical Center, Seoul 05505, Republic of Korea.
authors.forename: Seungjoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Neurosurgery, Asan Medical Center, Seoul 05505, Republic of Korea.
authors.forename: Jeong Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Republic of Korea.
authors.forename: Dong-Cheol
authors.initials: DC
authors.lastname: Woo
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea; Bio-Synergy Research Center, Daejeon 34141, Republic of Korea. Electronic address: dhlee@kaist.ac.kr.
authors.forename: Doheon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea. Electronic address: gykoh@kaist.ac.kr.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D011485:Protein Binding / Q000187:drug effects; D042787:Receptor, TIE-2 / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000037:antagonists & inhibitors*; D000077204:Temozolomide; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D003606:Dacarbazine; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic; D000077204:Temozolomide
keywords: M2-like TAM; Tie2 activation; angiopoietin-2; enhanced drug delivery; tumor microenvironment; tumor vasculature; tumor vessel normalization