title: Radioimmunotherapy of fibroblast activation protein positive tumors by rapidly internalizing antibodies.
abstract: OBJECTIVE
  Fibroblast activation protein (FAP) is a serine protease that has emerged as a promising target for cancer therapy, either by direct abrogation of its proinvasive activity or by specific targeting of FAP-expressing cells with cytotoxic immunoconjugates. We aimed to select novel human-mouse cross-reactive antibodies and to test suitability for tumor therapy as radioimmunoconjugates in a preclinical model.
  
  
  METHODS
  Human Fab fragments that bind to human and murine FAP were selected from an antibody phage library. Two candidates (ESC11 and ESC14) were engineered into fully human IgG1 antibodies and further characterized. We investigated the intracellular trafficking of ESC11 and ESC14 in live cells by confocal microscopy and analyzed the biodistribution and therapeutic effects of anti-FAP antibodies labeled with the β-emitting radionuclide (177)Lu in a melanoma xenograft nude mouse model. Results were compared with vF19, a humanized variant of an anti-FAP antibody that has been previously used in clinical trials.
  
  
  RESULTS
  The two antibodies bound selectively to both human and mouse FAP, with affinities in the low nanomolar range. Binding to FAP-expressing melanoma cells resulted in rapid internalization of FAP-antibody complexes. (177)Lu-labeled ESC11 specifically accumulated in melanoma xenografts in vivo, with a higher tumor uptake than ESC14 and vF19. Radioimmunotherapy with 8 MBq (177)Lu-labeled anti-FAP antibodies delayed growth of established tumors, whereas (177)Lu-ESC11 extended mouse survival more pronounced than (177)Lu-ESC14 and (177)Lu-vF19.
  
  
  CONCLUSIONS
  Our results show the potential of ESC11 and ESC14 as potent radioimmunoconjugates or antibody-drug conjugates for diagnostic and therapeutic use in patients with FAP-expressing tumors.
authors.affiliation: Division of Oncology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Eliane
authors.initials: E
authors.lastname: Fischer
authors.forename: Krishna
authors.initials: K
authors.lastname: Chaitanya
authors.forename: Thomas
authors.initials: T
authors.lastname: Wüest
authors.forename: Andreas
authors.initials: A
authors.lastname: Wadle
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Maries
authors.initials: M
authors.lastname: van den Broek
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Christoph
authors.initials: C
authors.lastname: Renner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000915:Antibody Affinity; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D010450:Endopeptidases; D018604:Epitope Mapping; D005260:Female; D018093:Gelatinases / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000378:metabolism / Q000532:radiotherapy*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D021381:Protein Transport; D016499:Radioimmunotherapy; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000911:Antibodies, Monoclonal; D010450:Endopeptidases; D018093:Gelatinases; D007074:Immunoglobulin G; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha