Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

Purpose

Endosialin/tumor endothelial marker-1 (TEM1) is an attractive theranostic target expressed by the microenvironment of a wide range of tumors, as well as by sarcoma and neuroblastoma cells. We report on the radiolabeling and preclinical evaluation of the scFv78-Fc, a fully human TEM1-targeting antibody fragment cross-reactive with mouse TEM1.

Procedures

The scFv78-Fc was conjugated with the chelator p-SCN-Bn-CHX-A”-DTPA, followed by labeling with indium-111. The number of chelators per molecule was estimated by mass spectrometry. A conventional saturation assay, extrapolated to infinite antigen concentration, was used to determine the immunoreactive fraction of the radioimmunoconjugate. The radiopharmaceutical biodistribution was assessed in immunodeficient mice grafted with Ewing’s sarcoma RD-ES and neuroblastoma SK-N-AS human TEM1-positive tumors. The full biodistribution studies were preceded by a dose-escalation experiment based on the simultaneous administration of the radiopharmaceutical with increasing amounts of unlabeled scFv78-Fc. Radiation dosimetry extrapolations to human adults were obtained from mouse biodistribution data according to established methodologies and additional assumptions concerning the impact of the tumor antigenic sink in the cross-species translation.

Results

[¹¹¹In]CHX-DTPA-scFv78-Fc was obtained with a radiochemical purity >?98 % after 1 h incubation at 42 °C and ultrafiltration. It showed good stability in human serum and >?70 % immunoreactive fraction. Biodistribution data acquired in tumor-bearing mice confirmed fast blood clearance and specific tumor targeting in both xenograft models. The radiopharmaceutical off-target uptake was predominantly abdominal. After a theoretical injection of [¹¹¹In]CHX-DTPA-scFv78-Fc to the reference person, the organs receiving the highest absorbed dose would be the spleen (0.876 mGy/MBq), the liver (0.570 mGy/MBq) and the kidneys (0.298 mGy/MBq). The total body dose and the effective dose would be 0.058 mGy/MBq and 0.116 mSv/MBq, respectively.

Conclusions

[¹¹¹In]CHX-DTPA-scFv78-Fc binds specifically to endosialin/TEM1 in vitro and in vivo. Dosimetry estimates are in the range of other monoclonal antibodies radiolabeled with indium-111. [¹¹¹In]CHX-DTPA-scFv78-Fc could be potentially translated into clinic.

     

A Hough transform global probabilistic approach to multiple-subject diffusion MRI tractography

A global probabilistic fiber tracking approach based on the voting process provided by the Hough transform is introduced in this work. The proposed framework tests candidate 3D curves in the volume, assigning to each one a score computed from the diffusion images, and then selects the curves with the highest scores as the potential anatomical connections. The algorithm avoids local minima by performing an exhaustive search at the desired resolution. The technique is easily extended to multiple subjects, considering a single representative volume where the registered high-angular resolution diffusion images (HARDI) from all the subjects are non-linearly combined, thereby obtaining population-representative tracts. The tractography algorithm is run only once for the multiple subjects, and no tract alignment is necessary. We present experimental results on HARDI volumes, ranging from simulated and 1.5T physical phantoms to 7T and 4T human brain and 7T monkey brain datasets.     

Validity of systemic lupus erythematosus disease activity score (SLE-DAS) for definition of lupus low disease activity state (LLDAS)

Clinical Rheumatology - SLE disease activity score (SLE-DAS) is a novel, rapid, continuous and comprehensive score that overcomes the drawbacks of SLEDAI-2 K. Low lupus disease activity...     

Kaposi’s sarcoma in a patient with severe relapsing polychondritis

This report describes the case of a young man who developed Kaposis sarcoma (KS) after corticosteroid treatment for severe tracheal involvement of relapsing polychondritis (RP). The etiopathogenetic mechanisms that may have led to the evolution of this unusual neoplasm are discussed. To our knowledge, this is the first case reported of concomitant RP and KS.     

Electronic Medical Records and Electronic Health Records: Overview for Nurse Practitioners

Electronic medical records (EMRs) and electronic health records (EHRs) have become essential systems by which nurse practitioners (NPs) communicate vital patient information to other members of the health care team as well as to patients. In this article we examine the important distinctions between EMRs and EHRs; review the genesis of these types of records; summarize applicable provisions of the Health Insurance Portability and Accountability Act from a recent legal case centered around NP utilization of EMRs and EHRs; address open patient access to medical information; and examine threats to security. Suggestions are offered on ways in which NPs can safeguard confidential patient information.     

Catheter-Associated Urinary Tract Infection by Pseudomonas aeruginosa Is Mediated by Exopolysaccharide-Independent Biofilms

Pseudomonas aeruginosa is an opportunistic human pathogen that is especially adept at forming surface-associated biofilms. P. aeruginosa causes catheter-associated urinary tract infections (CAUTIs) through biofilm formation on the surface of indwelling catheters. P. aeruginosa encodes three extracellular polysaccharides, PEL, PSL, and alginate, and utilizes the PEL and PSL polysaccharides to form biofilms in vitro; however, the requirement of these polysaccharides during in vivo infections is not well understood. Here we show in a murine model of CAUTI that PAO1, a strain harboring pel, psl, and alg genes, and PA14, a strain harboring pel and alg genes, form biofilms on the implanted catheters. To determine the requirement of exopolysaccharide during in vivo biofilm infections, we tested isogenic mutants lacking the pel, psl, and alg operons and showed that PA14 mutants lacking these operons can successfully form biofilms on catheters in the CAUTI model. To determine the host factor(s) that induces the ΔpelD mutant to form biofilm, we tested mouse, human, and artificial urine and show that urine can induce biofilm formation by the PA14 ΔpelD mutant. By testing the major constituents of urine, we show that urea can induce a pel-, psl-, and alg-independent biofilm. These pel-, psl-, and alg-independent biofilms are mediated by the release of extracellular DNA. Treatment of biofilms formed in urea with DNase I reduced the biofilm, indicating that extracellular DNA supports biofilm formation. Our results indicate that the opportunistic pathogen P. aeruginosa utilizes a distinct program to form biofilms that are independent of exopolysaccharides during CAUTI.