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General Approach for Tetramer Based Identification of Autoantigen Reactive B Cells: Characterization of La and snRNP Reactive B Cells in Autoimmune BXD2 Mice

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Paraburkholderia fungorum Chlamydia pneumoniae Mus musculus Betapolyomavirus macacae Caprine arthritis encephalitis virus Human betaherpesvirus 6 Human betaherpesvirus 5 Human herpesvirus 4 strain B95-8 Human T-cell lymphotrophic virus type 1 (isolate MT-2) Hepacivirus hominis Shigella flexneri human gammaherpesvirus 4 Human Endogenous Retrovirus IDDMK1,2-22 Mycobacterium gordonae Homo sapiens Human poliovirus 3 strain Sabin Mycobacterium avium subsp. paratuberculosis Helicobacter pylori Mycobacterium tuberculosis Human alphaherpesvirus 2 Coxsackievirus B4 Human alphaherpesvirus 1 Chlamydia trachomatis Mycobacterium avium subsp. paratuberculosis K-10 Streptococcus pyogenes Human herpesvirus 4 type 2 Human herpesvirus 4 type 1 Human adenovirus 12 Mycobacterium tuberculosis variant bovis Coxsackievirus B4 (strain E2) Trypanosoma cruzi Mycobacterium avium Hepatitis C virus isolate HC-J6 Human endogenous retrovirus K Coxsackievirus A9 Human rotavirus MP409 Haemophilus influenzae Proteus mirabilis Porphyromonas gingivalis Escherichia coli Yersinia enterocolitica Lactobacillus delbrueckii subsp. bulgaricus Klebsiella pneumoniae Porphyromonas gingivalis W83 Staphylococcus aureus A9635 Human immunodeficiency virus 1 Torque teno virus Human T-cell leukemia virus type I Prochlorococcus marinus str. MIT 9202 Staphylococcus aureus Coxsackievirus A20

PROVIDER: GSE65290 | GEO | 2015/02/28

SECONDARY ACCESSION(S): PRJNA273630

REPOSITORIES: GEO

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Project description:BackgroundTo 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.Methodology/principal findingsImmunoconjugates 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/significanceWe 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.

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General Approach for Tetramer Based Identification of Autoantigen Reactive B Cells: Characterization of La and snRNP Reactive B Cells in Autoimmune BXD2 Mice

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