Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors

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dc.contributor.authorAl-ejeh, F.
dc.contributor.authorDarby, J.
dc.contributor.authorBrown, M.
dc.contributor.editorBoswell, A.
dc.date.issued2009
dc.description.abstractTo 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 (90Y)-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. Methodology/Principal Findings: 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 90Y. Mice bearing established subcutaneous tumors were treated with 90Y-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 90Y-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/Significance: 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®.
dc.description.statementofresponsibilityFares Al-Ejeh, Jocelyn M. Darby and Michael P. Brown
dc.identifier.citationPLoS One, 2009; 4(2):1-13
dc.identifier.doi10.1371/journal.pone.0004630
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.orcidBrown, M. [0000-0002-5796-1932] [0000-0002-6678-1407]
dc.identifier.urihttp://hdl.handle.net/2440/60349
dc.language.isoen
dc.publisherPublic Library of Science
dc.rights© 2009 Al-Ejeh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.urihttps://doi.org/10.1371/journal.pone.0004630
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice
dc.subjectCarcinoma, Lewis Lung
dc.subjectCisplatin
dc.subjectCyclophosphamide
dc.subjectHeterocyclic Compounds, 1-Ring
dc.subjectEtoposide
dc.subjectRibonucleoproteins
dc.subjectDeoxycytidine
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectAntibodies, Monoclonal
dc.subjectAutoantigens
dc.subjectRadioimmunotherapy
dc.subjectCombined Modality Therapy
dc.subjectImmunohistochemistry
dc.subjectGemcitabine
dc.subjectSS-B Antigen
dc.titleChemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors
dc.typeJournal article
pubs.publication-statusPublished

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