Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors.
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.
Al-Ejeh
Fares
F
Experimental Therapeutics Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
Darby
Jocelyn M
JM
Brown
Michael P
MP
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
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