title: Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors.
abstract: BACKGROUND
  To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 ((90)Y)-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment.
  
  
  RESULTS
  Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and then radiolabeled with (90)Y. Mice bearing established subcutaneous tumors were treated with (90)Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2) model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of (90)Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants.
  
  
  CONCLUSIONS
  We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4-targeted ionizing radiation induces additional cycles of tumor cell death, which further augments DAB4 binding to produce a tumor-lethal 'genotoxic chain reaction'. Clinically, this approach may be useful as consolidation treatment after a drug-induced cell death among (small-volume) metastatic deposits, the commonest cause of cancer death. This article is part II of a two-part series providing proof-of-concept for the diagnostic and therapeutic use of the DAB4 clone of the La-specific monoclonal antibody, APOMAB.
authors.affiliation: Experimental Therapeutics Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
authors.forename: Fares
authors.initials: F
authors.lastname: Al-Ejeh
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Darby
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001324:Autoantigens / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005047:Etoposide / Q000008:administration & dosage; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016499:Radioimmunotherapy; D012261:Ribonucleoproteins / Q000276:immunology*; D000093542:Gemcitabine; D000097585:SS-B Antigen
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D002945:Cisplatin; D003520:Cyclophosphamide; D003841:Deoxycytidine; D005047:Etoposide; D006573:Heterocyclic Compounds, 1-Ring; D012261:Ribonucleoproteins; D000093542:Gemcitabine; D000097585:SS-B Antigen; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid