title: Simultaneous targeting of prostate stem cell antigen and prostate-specific membrane antigen improves the killing of prostate cancer cells using a novel modular T cell-retargeting system.
abstract: BACKGROUND
  Recently, we described a novel modular platform technology in which T cell-recruitment and tumor-targeting domains of conventional bispecific antibodies are split to independent components, a universal effector module (EM) and replaceable monospecific/monovalent target modules (TMs) that form highly efficient T cell-retargeting complexes. Theoretically, our unique strategy should allow us to simultaneously retarget T cells to different tumor antigens by combining the EM with two or more different monovalent/monospecific TMs or even with bivalent/bispecific TMs, thereby overcoming limitations of a monospecific treatment such as the selection of target-negative tumor escape variants.
  
  
  METHODS
  In order to advance our recently introduced prostate stem cell antigen (PSCA)-specific modular system for a dual-targeting of prostate cancer cells, two additional TMs were constructed: a monovalent/monospecific TM directed against the prostate-specific membrane antigen (PSMA) and a bivalent/bispecific TM (bsTM) with specificity for PSMA and PSCA. The functionality of the novel dual-targeting strategies was analyzed by performing T cell activation and chromium release assays.
  
  
  RESULTS
  Similar to the PSCA-specific modular system, the novel PSMA-specific modular system mediates an efficient target-dependent and -specific tumor cell lysis at low E:T ratios and picomolar Ab concentrations. Moreover, by combination of the EM with either the bispecific TM directed to PSMA and PSCA or both monospecifc TMs directed to either PSCA or PSMA, dual-specific targeting complexes were formed which allowed us to kill potential escape variants expressing only one or the other target antigen.
  
  
  CONCLUSIONS
  Overall, the novel modular system represents a promising tool for multiple tumor targeting.
authors: Medical Faculty 'Carl Gustav Carus' TU Dresden, Institute of Immunology, Dresden, Germany.
authors: Claudia
authors: C
authors: Arndt
authors: Anja
authors: A
authors: Feldmann
authors: Stefanie
authors: S
authors: Koristka
authors: Marc
authors: M
authors: Cartellieri
authors: Maria
authors: M
authors: Dimmel
authors: Armin
authors: A
authors: Ehninger
authors: Gerhard
authors: G
authors: Ehninger
authors: Michael
authors: M
authors: Bachmann
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000276:immunology; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007167:Immunotherapy; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: T cell redirection; dual-targeting; immunotherapy; recombinant antibody