title: Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts.
abstract: OBJECTIVE
  Invasion and metastasis of malignant epithelial cells into normal tissues is accompanied by adaptive changes in the mesenchyme-derived supporting stroma of the target organs. Altered gene expression in these nontransformed stromal cells provides potential targets for therapy. The present study was undertaken to determine the antitumor effects of an antibody-conjugate against fibroblast activation protein-alpha, a cell surface protease of activated tumor fibroblasts.
  
  
  METHODS
  A novel antibody-maytansinoid conjugate, monoclonal antibody (mAb) FAP5-DM1, was developed to target a shared epitope of human, mouse, and cynomolgus monkey fibroblast activation protein-alpha, enabling preclinical efficacy and tolerability assessments. We have used stroma-rich models in immunodeficient mice, which recapitulate the histotypic arrangement found in human epithelial cancers.
  
  
  RESULTS
  Treatment with mAb FAP5-DM1 induced long-lasting inhibition of tumor growth and complete regressions in xenograft models of lung, pancreas, and head and neck cancers with no signs of intolerability. Analysis of chemically distinct conjugates, resistance models, and biomarkers implicates a unique mode of action, with mitotic arrest and apoptosis of malignant epithelial cells coupled to disruption of fibroblastic and vascular structures.
  
  
  CONCLUSIONS
  We show that mAb FAP5-DM1 combines excellent efficacy and tolerability and provides a first assessment of the mode of action of a novel drug candidate for tumor stroma targeting, thus encouraging further development toward clinical testing of this treatment paradigm.
authors.affiliation: Boehringer Ingelheim Austria GmbH, Austria.
authors.forename: Elinborg
authors.initials: E
authors.lastname: Ostermann
authors.forename: Pilar
authors.initials: P
authors.lastname: Garin-Chesa
authors.forename: Karl Heinz
authors.initials: KH
authors.lastname: Heider
authors.forename: Milena
authors.initials: M
authors.lastname: Kalat
authors.forename: Herbert
authors.initials: H
authors.lastname: Lamche
authors.forename: Christina
authors.initials: C
authors.lastname: Puri
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Rettig
authors.forename: Guenther R
authors.initials: GR
authors.lastname: Adolf
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology*; D014408:Biomarkers, Tumor / Q000276:immunology*; D010450:Endopeptidases; D005347:Fibroblasts / Q000276:immunology*; D018093:Gelatinases; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008252:Macaca fascicularis; D008453:Maytansine / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D008565:Membrane Proteins; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D012697:Serine Endopeptidases / Q000276:immunology*; D020349:Surface Plasmon Resonance; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D018796:Immunoconjugates; D008453:Maytansine; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha