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Infections with helminth parasites prevent/attenuate auto-inflammatory disease. Here we show that molecules secreted by a helminth parasite could prevent Type 1 Diabetes (T1D) in nonobese diabetic (NOD) mice. When delivered at 4 weeks of age (coincident with the initiation of autoimmunity), the excretory/secretory products of Fasciola hepatica (FhES) prevented the onset of T1D, with 84% of mice remaining normoglycaemic and insulitis-free at 30 weeks of age. Disease protection was associated with suppression of IFN-γ secretion from autoreactive T cells and a switch to the production of a regulatory isotype (from IgG2a to IgG1) of autoantibody. Following FhES injection, peritoneal macrophages converted to a regulatory M2 phenotype, characterised by increased expression levels of Ym1, Arg-1, TGFβ and PD-L1. Expression of these M2 genetic markers increased in the pancreatic lymph nodes and the pancreas of FhES-treated mice. In vitro, FhES-stimulated M2 macrophages induced the differentiation of Tregs from splenocytes isolated from naïve NOD mice. Collectively, our data shows that FhES contains immune-modulatory molecules that mediate protection from autoimmune diabetes via the induction and maintenance of a regulatory immune environment. [ABSTRACT FROM AUTHOR]

Objectives: Miltuximab ® is a chimeric antibody targeting Glypican-1 (GPC-1), a cell surface antigen which is overexpressed in solid cancers. Miltuximab ® has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. This first in human study used Miltuximab ® radiolabelled with Gallium-67 ([ 67 Ga]Ga-DOTA-Miltuximab ® ). The primary study endpoint was to establish safety and tolerability of Miltuximab ® . Secondary endpoints were biodistribution, tumour targeting and pharmacokinetic analysis., Methods: Four cohorts of three patients (9 with advanced prostate cancer, 2 with pancreatic and 1 with bladder cancer) were dosed with 1 mg, ~250 MBq of [ 67 Ga]Ga-DOTA-Miltuximab ® . Cohort 1 received [ 67 Ga]Ga-DOTA-Miltuximab ® alone, while cohorts 2-4 were pre-infused with increasing doses (3.5, 11.5 and 24 mg, respectively) of unlabelled Miltuximab ® -DOTA 1 hour prior to [ 67 Ga]Ga-DOTA-Miltuximab ® . Safety and tolerability were assessed by clinical and standard laboratory assessments. Patients underwent whole body gamma-camera scans and SPECT/CT scans up to 144 h post-infusion. Total organ radiation exposure was determined by dosimetry of whole-body gamma scans., Results: The dosing regimen was well tolerated, with no drug-related adverse events observed. Liver and spleen uptake of [ 67 Ga]Ga-DOTA-Miltuximab ® was observed. Liver uptake was reduced by pre-infusion of unlabelled Miltuximab ® -DOTA. Dosimetry analysis showed a favorable exposure profile. [ 67 Ga]Ga-DOTA-Miltuximab ® targeting to tumour sites was observed in two prostate cancer patients who had failed enzalutamide treatment. Higher doses of unlabelled antibody achieved lower liver uptake and increased antibody serum half life., Conclusions: This study is the first in human for Miltuximab ® a first in class antibody targeting GPC-1. The trial met its primary endpoint of safety, demonstrating its potential as a safe and tolerable monoclonal antibody. This safety data, together with targeting to tumour lesions and biodistribution information supports the further clinical development of Miltuximab ® as a theranostic agent in a planned Phase I human trial., (© 2021 mums.ac.ir All rights reserved.)

Glioblastoma (GBM) is one of the most aggressive tumors and its 5-year survival is approximately 5%. Fluorescence-guided surgery (FGS) improves the extent of resection and leads to better prognosis. Molecular near-infrared (NIR) imaging appears to outperform conventional FGS, however, novel molecular targets need to be identified in GBM. Proteoglycan glypican-1 (GPC-1) is believed to be such a target as it is highly expressed in GBM and is associated with poor prognosis. We hypothesize that an anti-GPC-1 antibody, Miltuximab ® , conjugated with the NIR dye, IRDye800CW (IR800), can specifically accumulate in a GBM xenograft and provide high-contrast in vivo fluorescent imaging in rodents following systemic administration. Miltuximab ® was conjugated with IR800 and intravenously administered to BALB/c nude mice bearing a subcutaneous U-87 GBM hind leg xenograft. Specific accumulation of Miltuximab ® -IR800 in subcutaneous xenograft tumor was detected 24 h later using an in vivo fluorescence imager. The conjugate did not cause any adverse events in mice and caused strong fluorescence of the tumor with tumor-to-background ratio (TBR) reaching 10.1 ± 2.8. The average TBR over the 10-day period was 5.8 ± 0.6 in mice injected with Miltuximab ® -IR800 versus 2.4 ± 0.1 for the control group injected with IgG-IR800 ( p = 0.001). Ex vivo assessment of Miltuximab ® -IR800 biodistribution confirmed its highly specific accumulation in the tumor. The results of this study confirm that Miltuximab ® -IR800 holds promise for intraoperative fluorescence molecular imaging of GBM and warrants further studies.