title: Characterization of the first fully human anti-TEM1 scFv in models of solid tumor imaging and immunotoxin-based therapy.
abstract: Tumor endothelial marker 1 (TEM1) has been identified as a novel surface marker upregulated on the blood vessels and stroma in many solid tumors. We previously isolated a novel single-chain variable fragment (scFv) 78 against TEM1 from a yeast display scFv library. Here, we evaluated the potential applications of scFv78 as a tool for tumor molecular imaging, immunotoxin-based therapy and nanotherapy. Epitope mapping, three-dimensional structure docking and affinity measurements indicated that scFv78 could bind to both human and murine TEM1, with equivalent affinity, at a well-conserved conformational epitope. The rapid internalization of scFv78 and scFv78-labeled nanoparticles was triggered after specific TEM1 binding. The scFv78-saporin immunoconjugate also exerted dose-dependent cytotoxicity with high specificity to TEM1-positive cells in vitro. Finally, specific and sensitive tumor localization of scFv78 was confirmed with optical imaging in a tumor mouse model that has highly endogenous mTEM1 expression in the vasculature. Our data indicated that scFv78, the first fully human anti-TEM1 recombinant antibody, recognizes both human and mouse TEM1 and has unique and favorable features that are advantageous for the development of imaging probes or antibody-toxin conjugates for a large spectrum of human TEM1-positive solid tumors.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangdong, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Yang
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.|School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Xuhua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Shrey
authors.initials: S
authors.lastname: Sukhadia
authors.affiliation: Ludwig Cancer Research Center, Lausanne, Switzerland.
authors.forename: Najia
authors.initials: N
authors.lastname: Musolino
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Huijing
authors.initials: H
authors.lastname: Bao
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tingtao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Qirui
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Santoro
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Hu
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ruihe
authors.initials: R
authors.lastname: Lin
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Chemistry and Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. qinweij@fmmu.edu.cn.
authors.forename: Weijun
authors.initials: W
authors.lastname: Qin
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. zhaoaizhi@gmail.com.|University City Science Center, Room 544, 3624 Market Street, Philadelphia, PA, 19104, USA. zhaoaizhi@gmail.com.
authors.forename: Aizhi
authors.initials: A
authors.lastname: Zhao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D000922:Immunotoxins / Q000276:immunology* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C078203:CD248 protein, human; D000939:Epitopes; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D009363:Neoplasm Proteins; C509258:tumor endothelial marker 1, mouse
keywords: Immunotoxin; Nanoparticle; Optical imaging; TEM1; scFv