title: Antibody-based tumor vascular theranostics targeting endosialin/TEM1 in a new mouse tumor vascular model.
abstract: Tumor endothelial marker 1 (TEM1, endosialin) is a tumor vascular marker with significant diagnostic and therapeutic potential. However, in vivo small animal models to test affinity reagents specifically targeted to human (h)TEM1 are limited. We describe a new mouse tumor model where tumor vascular endothelial cells express hTEM1 protein.
  
  
  METHODS
  Immortalized murine endothelial cells MS1 were engineered to express hTEM1 and firefly luciferase and were inoculated in nude mice either alone, to form hemangioma-like endothelial grafts, or admixed with ID8 ovarian tumor cells, to form chimeric endothelial-tumor cell grafts. MORAb-004, a monoclonal humanized IgG 1 antibody specifically recognizing human TEM1 was evaluated for targeted theranostic applications, i.e., for its ability to affect vascular grafts expressing hTEM1 as well as being a tool for molecular positron emission tomography (PET) imaging.
  
  
  RESULTS
  Naked MORAb-004 treatment of mice bearing angioma grafts or chimeric endothelial-tumor grafts significantly suppressed the ability of hTEM1-positive endothelial cells, but not control endothelial cells, to form grafts and dramatically suppressed local angiogenesis. In addition, highly efficient radioiodination of MORAb-004 did not impair its affinity for hTEM1, and [ (124)I]-MORAb-004-PET enabled non-invasive visualization of tumors enriched with hTEM1-positive, but not hTEM1 negative vasculature with high degree of specificity and sensitivity.
  
  
  CONCLUSIONS
  The development of a new robust endothelial graft model expressing human tumor vascular proteins will help accelerate the development of novel theranostics targeting the tumor vasculature, which exhibit affinity specifically to human targets but not their murine counterparts. Our results also demonstrate the theranostic potential of MORAb-004 as PET imaging tracer and naked antibody therapy for TEM1-positive tumor.
authors.affiliation: Ovarian Cancer Research Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute for Translational Medicine and Therapeutics; University of Pennsylvania; Philadelphia, PA USA; Division of Nuclear Medicine and Clinical Molecular Imaging; Department of Radiology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Chacko
authors.affiliation: Ovarian Cancer Research Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Hu
authors.affiliation: Ovarian Cancer Research Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Kosei
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Ovarian Cancer Research Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Swails
authors.affiliation: Morphotek, Inc.; Exton, PA USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Grasso
authors.affiliation: Department of Medicine, Hematology/Oncology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
authors.affiliation: Morphotek, Inc.; Exton, PA USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Nicolaides
authors.affiliation: Institute for Translational Medicine and Therapeutics; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
authors.affiliation: Division of Nuclear Medicine and Clinical Molecular Imaging; Department of Radiology; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Chaitanya R
authors.initials: CR
authors.lastname: Divgi
authors.affiliation: Ovarian Cancer Research Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000378:metabolism; D064593:Heterografts; D007457:Iodine Radioisotopes; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000628:therapy*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D007457:Iodine Radioisotopes; D009363:Neoplasm Proteins; D019275:Radiopharmaceuticals; C509258:tumor endothelial marker 1, mouse; C000604563:ontuxizumab
keywords: CD248; TEM1; anti-angiogenesis; antibody therapy; endosialin; immunoPET; tumor vasculature