Michel, A. L. | bioRxiv Science

bioRxiv2024

Targeted Alpha Therapy with Ac-Macropa-Isatuximab for CD38-positive Hematological Malignancies

BackgroundHematological malignancies include diverse cancers related to immune system cells and blood-forming tissue. Treatment resistance and relapse are common despite the introduction of novel therapeutics. Following the development of the PET probe [89Zr]Zr-DFO-isatuximab, targeting the overexpressed CD38 receptor, we developed [225Ac]Ac-Macropa-isatuximab for targeted alpha therapy in murine models of human multiple myeloma (MM) and lymphoma. MethodsIn vitro studies were performed using the CD38 expressing MM1.S (human MM) and Daudi (human lymphoma). Radiopharmaceutical therapy studies were performed in female NSG mice, and the disseminated disease models were established by intravenous injection of luciferase-transfected cells. Mice were randomized (n = 10 mice per cohort) and received a high activity (5.5 kBq) or low activity (2.7 kBq) of [225Ac]Ac-Macropa-Isatuximab in single or multiple cycles. Controls receiving untargeted [225Ac]Ac-Macropa-IgG or saline were included. Tumor burden was measured by bioluminescence imaging (BLI). Weight loss greater than 20% or leg paralysis were used as endpoints. Results[225Ac]Ac-Macropa-Isatuximab was obtained with high radiochemical yield and purity (>95%). It displayed high immunoreactivity and excellent stability in human serum over 10 days. The therapeutic effect of [225Ac]Ac-mcp-Isatuximab was significant for all the treatment cohorts compared to the saline control after administration of the first cycle. Low activities were better tolerated in general, resulting in extended median survivals. The most successful regimen in the MM model was the dual cycle of low activity, with a median survival of 60 days (P < 0.001). In the lymphoma model, the single high activity of 5.5 kBq and four low activity of 2.7 kBq resulted in similar median survivals of 143 days (P < 0.0001) and 147 days (P < 0.0001). These regimens resulted in complete responses with no detectable cancer cells in some cases. Remarkably, no significant kidney damage was observed in any of the models. Conclusion[225Ac]Ac-Macropa-Isatuximab selectively targets CD38, reducing tumor growth and, in some cases, tumor eradication, especially when applied in multiple cycles. Importantly, it has not been associated with significant toxicities at levels of administered activity required for therapeutic benefit, indicating its promise as a therapeutic option.

pharmacology and toxicology↗

bioRxiv2019

Risk practices for bovine tuberculosis transmission to cattle and livestock farming communities living at wildlife-livestock-human interface in northern KwaZulu Natal, South Africa

Bovine tuberculosis (bTB) is a disease of cattle that is transmitted through direct contact with an infected animal or ingestion of contaminated food or water. This study seeks to explore the local knowledge on the disease and establish the risk practices that lead to its transmission to cattle and humans (zoonotic TB) in a traditional livestock farming community with a history of bTB diagnosis in cattle and wildlife. Information was collected using a qualitative approach of Focus Group Discussions (FGDs) targeting household members of livestock farmers that owned either bTB infected or uninfected herds. We conducted fourteen FGDs (150 individuals) across four dip tanks that included the following categories of participants from cattle owning households: heads of households, cattle keepers, dip tank committee members and women. The qualitative data was managed using NVivo Version 12 Pro(R)software. Social and cultural practices were identified as major risky practices for bTB transmission to people, such as the consumption of undercooked meat, consumption of soured /raw milk and lack of protective measures during slaughtering of cattle. The acceptance of animals into a herd without bTB pre-movement testing following traditional practices (e.g. lobola, bride price, the temporary introduction of a bull for breeding), the sharing of grazing and watering points amongst the herds and with wildlife were identified as risky practices for bTB transmission to cattle. Overall, knowledge of bTB in cattle and modes of transmission to people and livestock was found to be high. However, the community was still involved in risky practices that expose people and cattle to bovine TB. An inter-disciplinary One Health approach that engages the community is recommended, to provide locally relevant interventions that allows the community to keep their traditional practices and socio-economic systems whilst avoiding disease transmission to cattle and people.\n\nAuthor summaryBovine tuberculosis (bTB) is a respiratory disease of cattle that is transmitted to other animals as well as humans (zoonotic TB) through direct contact with infected animals, and consumption of contaminated food (animal products) or water. The study explains the complexities of human-animal relations, reflects on how people understand and conceptualize risk of bovine tuberculosis (bTB) in an endemic area considering the economic value of livestock keeping as well as social and cultural practices of importance to the community. The results of this study identified socio-cultural practices that involved consumption of raw or undercooked animal products and handling of infected animal products during animal slaughter as major risky practices for bTB transmission to people. Introduction of animals into a herd without bTB testing for socio-cultural purposes and sharing of resources amongst the communal herd and with wildlife were identified as risky practices for bTB transmission to cattle. The findings of this study illustrate the need for a One Health strategy that develops appropriate public health policy and related education campaigns for the community as control of zoonotic TB in people depends on the successful control of bovine TB in cattle.

microbiology↗