**1. 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]. IFI can also have devastating effects on dogs and cats [2]. New effective treatments for IFI are needed for human and veterinary medicine to overcome resistance issues, issues associated with poor bioavailability, and the high cost of oral antifungals in dogs. Radioimmunotherapy (RIT) uses antigen–antibody interaction to deliver sufficient activities of ionizing radiation to cells to induce DNA double-strand breaks

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]. RIT offers several advantages over other therapeutics: (1) Due to the nature of ionizing radiation, RIT physically destroys the desired cells, and does not just abolish a single pathway; (2) the total cell destruction makes it very difficult for a drug resistance mechanism to develop; (3) RIT does not rely on a healthy immune system to be effective, making the immune status of the patient less important; (4) the specific nature of RIT means there are less off-target effects, which results in lower toxicity compared to that of conventional chemotherapies. However, RIT is still subject to radioresistance phenomena, especially for big solid tumors, and induces hematoxicity in some patients. Additionally, we were the first to show that microorganism-specific monoclonal antibodies can be a viable therapy for viral, bacterial, and fungal infections in an experimental environment ([4,5]). RIT for infections potentially offers higher specificity and lower toxicity than cancer RIT as it targets microbial antigens which have no or very little homology with human proteins. In contrast to cancer, where every cancerous cell must be destroyed either directly by crossfire and bystander effects or indirectly via abscopal effect to prevent the resurgence of the disease, low numbers of microbial cells remaining post RIT can be eliminated by the immune system. Previously, we theorized that beta-glucan, a surface-expressed antigen that is shared by many major IFI-causing pathogens, would make an ideal target for RIT [6]. To show this, we utilized *Cryptococcus neoformans* and *Candida albicans*, as they are highly present. The in vitro results demonstrated that when labeled with the alpha-particle-emitting radionuclide Bismuth-213 (213Bi) the antibodies to the pan-antigens killed a very high percentage (80–100%) of the fungal cells [7]. <sup>213</sup>Bi, an alpha-emitter with a short physical half-life of 46 min, delivers its radiation impact within a short period of time, which can match the doubling time of the majority of the fungal pathogens. It gives <sup>213</sup>Bi an advantage over other longer-lived alpha emitters such as Actinium-225. Next, we were able to show that this approach can be translated in vivo by infecting mice with *Blastomyces dermatitidis* and targeting the pan-antigen beta-glucan [8]. *B. dermatitidis* was chosen as an IFI model as it is endemic to parts of Canada and causes devastating infections in immunocompetent people, companion dogs, and immunocompromised patients [2]. In this work, we performed a safety study of <sup>213</sup>Bi-400-2 antibody in healthy dogs as a prelude for a clinical trial in companion dogs with invasive fungal infections.
