Horse IgG [FITC]

Objective Infections contribute to morbidity and mortality in systemic lupus erythematosus (SLE). UropathogenicEscherichia coli(UPEC) are known to trigger urinary tract infections (UTIs) and form biofilms, which are multicellular communities of bacteria that are strengthened by amyloids such as curli. We previously reported that curli naturally form complexes with bacterial extracellular DNA (eDNA), and these curli/eDNA complexes induce hallmark features of lupus in mouse models. The present study was undertaken to investigate whether anti-curli/eDNA complex antibodies play a role in the pathogenesis of SLE or development of flares in SLE. Methods In total, 96 SLE patients who met at least 4 Systemic Lupus International Collaborating Clinics disease criteria were investigated. Anti-curli/eDNA complex antibodies in the plasma were tested for both IgG and IgA subclasses. Results were compared to that in 54 age-, sex-, and race/ethnicity-matched healthy controls. Correlations of the levels of anti-curli/eDNA antibodies with clinical parameters, lupus disease status, and frequency of bacteriuria were assessed. Results Anti-curli/eDNA antibodies were detected in the plasma of SLE patients and healthy controls, and their levels correlated with the presence of asymptomatic persistent bacteriuria and occurrence of disease flares in lupus patients. Persistent bacteriuria contained curli-producing UPEC, and this was associated with an inflammatory phenotype. Finally, curli/eDNA complexes cross-reacted with lupus autoantigens, such as double-stranded DNA, in binding autoantibodies. Conclusion These results suggest that UTIs and persistent bacteriuria are environmental triggers of lupus and its flares. Antibodies against curli/eDNA could serve as a sign of systemic exposure to bacterial products in SLE.

Purpose Multiple myeloma (MM) is a bone marrow malignancy that remains mostly incurable. Elotuzumab is an FDA-approved therapeutic monoclonal antibody targeted to the cell surface glycoprotein CS1, which is overexpressed in MM cells. Identifying patients who will respond to CS1-targeted treatments such as elotuzumab requires the development of a companion diagnostic to assess the presence of CS1. Here, we evaluated [Zr-89]DFO-elotuzumab as a novel PET tracer for imaging CS1 expression in preclinical MM models. Methods Conjugation of desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) to elotuzumab enabled zirconium-89 radiolabeling. MM.1S-CG cells were intravenously injected in NOD SCID gamma (NSG) mice. Small animal PET imaging with [Zr-89]DFO-elotuzumab (1.11 MBq/mouse, 7 days post-injection), [Zr-89]DFO-IgG (1.11 MBq/mouse, 7 days post-injection), and [F-18]FDG (7-8 MBq, 1 h post-injection) was performed. Additionally, biodistribution of [Zr-89]DFO-elotuzumab post-imaging at 7 days was also done. In vivo specificity of [Zr-89]DFO-elotuzumab was further evaluated with a blocking study and ex vivo autoradiography. Results [Zr-89]DFO-elotuzumab was produced with high specific activity (56 +/- 0.75 MBq/nmol), radiochemical purity (99% +/- 0.5), and yield (93.3% +/- 1.5). Dissociation constant of 40.4 nM and receptor density of 126 fmol/mg was determined in MM.1S-CG cells. Compared to [Zr-89]DFO-IgG, [Zr-89]DFO-elotuzumab localized with a significantly higher standard uptake value in tumor-bearing bone tissue (8.59 versus 4.77). Blocking with unlabeled elotuzumab significantly reduced (P < 0.05) uptake of [Zr-89]DFO-elotuzumab in the bones. Importantly, while [F-18]FDG demonstrated similar uptake in the bone and muscle, [Zr-89]DFO-elotuzumab showed > 3-fold enhanced uptake in bones. Conclusion These data demonstrate the feasibility of [Zr-89]DFO-elotuzumab as a companion diagnostic for CS1-targeted therapies.