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.

Muath Helal,Rubin Jiao,Hilary Burgess,Kevin J H Allen,Elisabeth Snead,Ekaterina Dadachova,Mackenzie E Malo,Matthew Hutcheson

doi:10.3390/molecules25163604

Muath Helal, Rubin Jiao + Show 6 more

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https://doi.org/10.3390/molecules25163604

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Journal: Molecules (Basel, Switzerland)	Publication Date: Aug 8, 2020
Citations: 7	License type: CC BY 4.0

Affiliation: University of Saskatchewan

Abstract

Background: 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 Blastomyces dermatitidis with 213Bi-labeled antibody 400-2 to (1→3)-β-glucan. In this work, we performed a safety study of 213Bi-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. Methods: Three female beagle dogs (≈6.1 kg body weight) were treated intravenously with 155.3, 142.5, or 133.2 MBq of 213Bi-400-2 given as three subfractions over an 8 h period. RBC, WBC, platelet, and blood serum biochemistry parameters were measured periodically for 6 months post injection. Results: No significant acute or long-term side effects were observed after RIT injections; only a few parameters were mildly and transiently outside reference change value limits, and a transient atypical morphology was observed in the circulating lymphocyte population of two dogs. Conclusions: These results demonstrate the safety of systemic 213Bi-400-2 administration in dogs and provide encouragement to pursue evaluation of RIT of IFI in companion dogs.

Highlights

For immunosuppressed patients, such as those suffering from cancer or are post organ transplant, invasive fungal infections (IFI) can be devastating
These parameters are of particular importance for radiolabeled antibody-based treatment as they reflect possible reversible or nonreversible toxicity to the bone marrow. These parameters were within laboratory reference intervals at all time points and generally within the reference change value (RCV) limits throughout the duration of the study
The 213 Bi/225 Ac radionuclide generator was purchased from Oak Ridge National Laboratory (Oak Ridge, TN, USA). 213 Bi was eluted from the 213 Bi/225 Ac radionuclide generator using 300 μL 0.1 M hydroiodic acid (HI) solution followed by 300 μL milliQ H2 O [14]

Summary

Introduction

For immunosuppressed patients, such as those suffering from cancer or are post organ transplant, invasive fungal infections (IFI) can be devastating. As causes of both morbidity and mortality, cases of IFI have more than tripled since 1979, highlighting the need for treatment [1]. Molecules 2020, 25, 3604 and alter cell membrane and intracellular components for cell apoptosis while preserving healthy tissues This treatment has demonstrated efficacy in primarily nonsolid tumors such as non-Hodgkin lymphomas [3]. With the limited options available for therapy to treat invasive fungal infections (IFI), radioimmunotherapy (RIT) can potentially offer an effective alternative treatment. Conclusions: These results demonstrate the safety of systemic 213 Bi-400-2 administration in dogs and provide encouragement to pursue evaluation of RIT of IFI in companion dogs

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