title: Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature.
abstract: Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Seaman
authors.affiliation: Protein Interactions Section, Cancer and Inflammation Program (CIP), NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: BioMed Valley Discoveries, Inc, Kansas City, MO 64111, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Saha
authors.affiliation: BioMed Valley Discoveries, Inc, Kansas City, MO 64111, USA.
authors.forename: Xiaoyan M
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Yang
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA; Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Hilton
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA; Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Morris
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Szot
authors.affiliation: Transgenic Core Facility, MCGP, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Morris
authors.affiliation: Transgenic Core Facility, MCGP, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Swing
authors.affiliation: Neural Development Section, MCGP, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Abzena, Bristol, PA 19007, USA.
authors.forename: Sean W
authors.initials: SW
authors.lastname: Smith
authors.affiliation: Abzena, Bristol, PA 19007, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Degrado
authors.affiliation: Abzena, Bristol, PA 19007, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Borkin
authors.affiliation: Abzena, Bristol, PA 19007, USA.
authors.forename: Nareshkumar
authors.initials: N
authors.lastname: Jain
authors.affiliation: Immune Modulation Section, CIP, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Scheiermann
authors.affiliation: Protein Interactions Section, Cancer and Inflammation Program (CIP), NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Protein Interactions Section, Cancer and Inflammation Program (CIP), NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Protein Interactions Section, Cancer and Inflammation Program (CIP), NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Li
authors.affiliation: BioMed Valley Discoveries, Inc, Kansas City, MO 64111, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Welsch
authors.affiliation: BioMed Valley Discoveries, Inc, Kansas City, MO 64111, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: DeCrescenzo
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Chaudhary
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA.
authors.forename: Enrique
authors.initials: E
authors.lastname: Zudaire
authors.affiliation: Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA; Hematopoiesis and Stem Cell Biology Section, MCGP, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Klarmann
authors.affiliation: Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, NCI, Frederick, MD 21702, USA; Hematopoiesis and Stem Cell Biology Section, MCGP, NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Keller
authors.affiliation: Protein Interactions Section, Cancer and Inflammation Program (CIP), NCI, NIH, Frederick, MD 21702, USA.
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.affiliation: Tumor Angiogenesis Unit, Mouse Cancer Genetics Program (MCGP), National Cancer Institute (NCI), NIH, Frederick, MD 21702, USA. Electronic address: stcroixb@mail.nih.gov.
authors.forename: Brad
authors.initials: B
authors.lastname: St Croix
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D060887:B7 Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D001569:Benzodiazepines / Q000494:pharmacology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D009842:Oligopeptides / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000970:Antineoplastic Agents; D060887:B7 Antigens; C423237:CD276 protein, human; C486038:Cd276 protein, mouse; D018796:Immunoconjugates; D009842:Oligopeptides; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; C495575:monomethyl auristatin E
keywords: ADC; Abcb1; B7H3; P-glycoprotein; P-gp; PBD; TEM; angiogenesis; cancer; endothelium