In Vitro and In Vivo Comparison of Random versus Site-Specific Conjugation of Bifunctional Chelating Agents to the CD33-Binding Antibody for Use in Alpha- and Beta-Radioimmunotherapy.

Radiometal chelator conjugation is a cornerstone of radioimmunotherapy (RIT). Continued interest in selective placement of chelators remains an active topic of discussion in the field. With several simple site-specific methods being recently reported, it was of interest to investigate the benefits and potential drawbacks of the site-specific method with a full comparison to a more typical random conjugation method that is currently utilized in clinical applications.

Persistent flat band splitting and strong selective band renormalization in a kagome magnet thin film.

Magnetic kagome materials provide a fascinating playground for exploring the interplay of magnetism, correlation and topology. Many magnetic kagome systems have been reported including the binary FeX (X = Sn, Ge; m:n = 3:1, 3:2, 1:1) family and the rare earth RMnSn (R = rare earth) family, where their kagome flat bands are calculated to be near the Fermi level in the paramagnetic phase. While partially filling a kagome flat band is predicted to give rise to a Stoner-type ferromagnetism, experimental visualization of the magnetic splitting across the ordering temperature has not been reported for any of these systems due to the high ordering temperatures, hence leaving the nature of magnetism in kagome magnets an open question.

The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors.

We previously found that chronic adenosine A1 receptor stimulation with N-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, a hallmark of Parkinson's disease. Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood-brain barrier and tested its ability to bind α-synuclein, reducing misfolding, behavioral abnormalities, and neurodegeneration in our rodent model. Behavioral tests and histological stains assessed neuroprotective effects of the dimer compound.

Initial insights into the interaction of antibodies radiolabeled with Lutetium-177 and Actinium-225 with tumor microenvironment in experimental human and canine osteosarcoma.

Background: Osteosarcoma (OS) is a prevalent primary bone cancer affecting both humans and canines. This study describes initial insights into the interaction of the human monoclonal antibody IF3 to an insulin-like growth factor 2 receptor (IGF2R) radiolabeled with either alpha-emitting Actinium-225 (Ac) or beta-emitting Lutetium-177 (Lu) radionuclides with the OS cells and tumor microenvironment (TME) in experimental human and canine OS.

Basic Procedures: SCID mice bearing canine Gracie or human OS-33 OS tumors were treated with Lu- or Ac-labeled IF3 antibody, sacrificed at 24, 72 or 168 h post-treatment and their tumors were analyzed by immunohistochemistry (IHC) for the presence of OS cells, various elements of TME as well as for the double DNA strand breaks with γH2AX and caspase 3 assays.

Antibody-Mediated Depletion of Autoreactive T Lymphocytes through PD-1 Improves Disease Outcomes and Visualizes T Cell Activation in Experimental Autoimmune Encephalomyelitis.

Long-term therapeutic outcomes of multiple sclerosis (MS) remain hindered by the chronic nature of immune cell stimulation toward self-antigens. Development of novel methods to target and deplete autoreactive T lymphocytes remains an attractive target for therapeutics for MS. We developed a programmed cell death 1 (PD-1)-targeted radiolabeled mAb and assessed its ability to deplete activated PD-1+ T lymphocytes in vitro and its ability to reduce disease burden of the myelin oligodendrocyte glycoprotein 35-55 experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice.

Radioimmunotherapy as a pathogen-agnostic treatment method for opportunistic mucormycosis infections.

Invasive fungal infections (IFIs) such as mucormycosis are causing devastating morbidity and mortality in immunocompromised patients as anti-fungal agents do not work in the setting of a suppressed immune system. The coronavirus disease 2019 (COVID-19) pandemic has created a novel landscape for IFIs in post-pandemic patients, resulting from severe immune suppression caused by COVID-19 infection, comorbidities (diabetes, obesity) and immunosuppressive treatments such as steroids. The antigen-antibody interaction has been employed in radioimmunotherapy (RIT) to deliver lethal doses of ionizing radiation emitted by radionuclides to targeted cells and has demonstrated efficacy in several cancers.

Hippocampal firing fields anchored to a moving object predict homing direction during path-integration-based behavior.

Homing based on path integration (H-PI) is a form of navigation in which an animal uses self-motion cues to keep track of its position and return to a starting point. Despite evidence for a role of the hippocampus in homing behavior, the hippocampal spatial representations associated with H-PI are largely unknown. Here we developed a homing task (AutoPI task) that required a mouse to find a randomly placed lever on an arena before returning to its home base.

Weyl nodal ring states and Landau quantization with very large magnetoresistance in square-net magnet EuGa.

Magnetic topological semimetals allow for an effective control of the topological electronic states by tuning the spin configuration. Among them, Weyl nodal line semimetals are thought to have the greatest tunability, yet they are the least studied experimentally due to the scarcity of material candidates. Here, using a combination of angle-resolved photoemission spectroscopy and quantum oscillation measurements, together with density functional theory calculations, we identify the square-net compound EuGa as a magnetic Weyl nodal ring semimetal, in which the line nodes form closed rings near the Fermi level.

Comparative Molecular Characterization and Pharmacokinetics of IgG1-Fc and Engineered Fc Human Antibody Variants to Insulin-like Growth Factor 2 Receptor (IGF2R).

Novel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously developed a fully human antibody, named IF3, that binds to insulin-like growth factor 2 receptor (IGF2R).

A Theranostic Approach to Imaging and Treating Melanoma with Pb/Pb-Labeled Antibody Targeting Melanin.

Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several immunotherapeutic agents into the clinic over the past decade, inspiring the development of novel therapeutics and the exploration of combination therapies. Our investigations target melanin pigment with melanin-specific radiolabeled antibodies as a strategy to treat metastatic melanoma. In this study, a theranostic approach was applied by first labeling a chimeric antibody targeting melanin, c8C3, with the SPECT radionuclide Pb for microSPECT/CT imaging of C57Bl6 mice bearing B16-F10 melanoma tumors.

Image-Based Dosimetry in Dogs and Cross-Reactivity with Human Tissues of IGF2R-Targeting Human Antibody.

Background: Osteosarcoma (OS) represents the most common primary bone tumor in humans and in companion dogs, being practically phenotypically identical. There is a need for effective treatments to extend the survival of patients with OS. Here, we examine the dosimetry in beagle dogs and cross-reactivity with human tissues of a novel human antibody, IF3, that targets the insulin growth factor receptor type 2 (IGF2R), which is overexpressed on OS cells, making it a candidate for radioimmunotherapy of OS.

An HPLC-UV validated bioanalytical method for measurement of phase 1 kinetics of α-synuclein binding bifunctional compounds.

Aggregates of the protein α-synuclein are associated with pathophysiology of Parkinson's disease and are present in Lewy Bodies found in the brains of Parkinson's patients. We previously demonstrated that bifunctional compounds composed of caffeine linked via a six carbon chain to either 1-aminoindan (C-6-I) or nicotine (C-6-N) bind α-synuclein and protect yeast cells from α-synuclein mediated toxicity.A critical step in development of positron emission tomography (PET) probes for neurodegenerative diseases is evaluation of their metabolic stability.

In Vitro and In Vivo Characterization of Zirconium-Labeled Lintuzumab Molecule.

Positron emission tomography (PET) imaging is a powerful non-invasive method to determine the in vivo behavior of biomolecules. Determining biodistribution and pharmacokinetic (PK) properties of targeted therapeutics can enable a better understanding of in vivo drug mechanisms such as tumor uptake, off target accumulation and clearance. Zirconium-89 (Zr) is a readily available tetravalent PET-enabling radiometal that has been used to evaluate the biodistribution and PK of monoclonal antibodies.

Targeting Melanin in Melanoma with Radionuclide Therapy.

Nearly 100,000 individuals are expected to be diagnosed with melanoma in the United States in 2022. Treatment options for late-stage metastatic disease up until the 2010s were few and offered only slight improvement to the overall survival. The introduction of B-RAF inhibitors and anti-CTLA4 and anti-PD-1/PD-L1 immunotherapies into standard of care brought measurable increases in the overall survival across all stages of melanoma.

Radioimmunotherapy Targeting IGF2R on Canine-Patient-Derived Osteosarcoma Tumors in Mice and Radiation Dosimetry in Canine and Pediatric Models.

Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors.

Virulence Genotype and Phenotype of Multiple Antimicrobial-Resistant Escherichia coli Isolates from Broilers Assessed from a "One-Health" Perspective.

Abstract: Extraintestinal pathogenic Escherichia coli (ExPEC) include several serotypes that have been associated with colibacillosis in poultry and with urinary tract infections (UTIs) and newborn meningitis in humans. In this study, 57 antimicrobial-resistant E. coli from apparently healthy broiler chickens were characterized for their health and safety risks.

Employing metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds.

A challenge in the development of novel F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the F radioisotope. Metabolic loss of F from PET probes can lead to misleading biodistribution data as displaced F can accumulate in various tissues.In this study we report on hepatic microsomal metabolism of novel caffeine containing bifunctional compounds (C-6-I, C-6-N, C-6-C) that can prevent aggregation of α-synuclein, which is associated with the pathophysiology of Parkinson's disease.

Novel Human Antibodies to Insulin Growth Factor 2 Receptor (IGF2R) for Radioimmunoimaging and Therapy of Canine and Human Osteosarcoma.

Etiological and genetic drivers of osteosarcoma (OS) are not well studied and vary from one tumor to another; making it challenging to pursue conventional targeted therapy. Recent studies have shown that cation independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R) is consistently overexpressed in almost all of standard and patient-derived OS cell lines, making it an ideal therapeutic target for development of antibody-based drugs. Monoclonal antibodies, targeting IGF2R, can be conjugated with alpha- or beta-emitter radionuclides to deliver cytocidal doses of radiation to target IGF2R expression in OS.

Correction: Upregulation of annexin A1 protein expression in the intratumoral vasculature of human non-small-cell lung carcinoma and rodent tumor models.

[This corrects the article DOI: 10.1371/journal.pone.

Commercially Available Blocking Oligonucleotides Effectively Suppress Unwanted Hemolysis-Related miRNAs in a Large Whole-Blood RNA Cohort.

When sequencing small RNA libraries derived from whole blood, the most abundant microRNAs (miRs) detected are often miR-486-5p, miR-451a, and miR-92a-3p. These highly expressed erythropoietic miRs are released into the sample from red blood cell hemolysis. Next-generation sequencing of these unwanted miRs leads to a waste in sequencing cost and diminished detection of lowly expressed miRNAs, including many potential miRNA biomarkers.

Antibiotic Resistance in Shiga Toxigenic Isolates from Surface Waters and Sediments in a Mixed Use Urban Agricultural Landscape.

Antibiotic resistance (AR) phenotypes and acquired resistance determinants (ARDs) detected by in silico analysis of genome sequences were examined in 55 Shiga toxin-producing (STEC) isolates representing diverse serotypes recovered from surfaces waters and sediments in a mixed use urban/agricultural landscape in British Columbia, Canada. The isolates displayed decreased susceptibility to florfenicol (65.5%), chloramphenicol (7.

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models.

Purpose: Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low-dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. Actinium-lintuzumab ( Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single-agent activity in relapsed/refractory AML.

Mechanistic Insights into Synergy between Melanin-Targeting Radioimmunotherapy and Immunotherapy in Experimental Melanoma.

Melanoma incidence continues to rise, and while therapeutic approaches for early stage cases are effective, metastatic melanoma continues to be associated with high mortality. Immune checkpoint blockade (ICB) has demonstrated clinical success with approved drugs in cohorts of patients with metastatic melanoma and targeted radionuclide therapy strategies showed promise in several clinical trials against various cancers including metastatic melanoma. This led our group to investigate the combination of these two treatments which could be potentially offered to patients with metastatic melanoma not responsive to ICB alone.

Targeted lymphodepletion with a CD45-directed antibody radioconjugate as a novel conditioning regimen prior to adoptive cell therapy.

Chimeric antigen receptor (CAR) T cell therapies, and adoptive cell therapy (ACT) in general, represent one of the most promising anti-cancer strategies. Conditioning has been shown to improve the immune homeostatic environment to enable successful ACT or CAR-T engraftment and expansion following infusion, and represents potential point of intervention to decrease serious toxicities following CAR-T treatment. In contrast to relatively non-specific chemotherapy-derived lymphodepletion, targeted lymphodepletion with radioimmunotherapy (RIT) directed to CD45 may be a safer and more effective alternative to target and deplete immune cells.

Safety Evaluation of an Alpha-Emitter Bismuth-213 Labeled Antibody to (1→3)-β-Glucan in Healthy Dogs as a Prelude for a Trial in Companion Dogs with Invasive Fungal Infections.

: With the limited options available for therapy to treat invasive fungal infections (IFI), radioimmunotherapy (RIT) can potentially offer an effective alternative treatment. Microorganism-specific monoclonal antibodies have shown promising results in the experimental treatment of fungal, bacterial, and viral infections, including our recent and encouraging results from treating mice infected with with Bi-labeled antibody 400-2 to (1→3)-β-glucan. In this work, we performed a safety study of Bi-400-2 antibody in healthy dogs as a prelude for a clinical trial in companion dogs with acquired invasive fungal infections and later on in human patients with IFI.