Department of Biology, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
University of Ottawa Heart Institute, Ottawa, ON, Canada; Department of Chemistry and Biomolecular Sciences, Ottawa, ON, Canada.
Nucl Med Biol. 2024 May-Jun;132-133:108908. doi: 10.1016/j.nucmedbio.2024.108908. Epub 2024 Mar 28.
Site-specific immunomodulators (SSIs) are a novel class of therapeutics made from inactivated bacterial species designed to regulate the innate immune system in targeted organs. QBECO is a gut-targeted SSI that is being advanced clinically to treat and/or prevent inflammatory bowel disease, cancer, and serious infections of the gastrointestinal (GI) tract and proximal organs, and QBKPN is a lung-targeted SSI that is in clinical development for the treatment and/or prevention of chronic inflammatory lung disease, lung cancers and respiratory tract infections. While these SSIs have demonstrated both safety and proof-of-concept in preclinical and clinical studies, detailed understanding of their trafficking and biodistribution is yet to be fully characterized.
QBECO and QBKPN were radiolabeled with [Zr] and injected subcutaneously into healthy mice. The mice underwent Positron Emission Tomography (PET) imaging every day for eight days to track biodistribution of the SSIs. Tissue from the site of injection was collected and immunohistologically probed for immune cell infiltration.
Differential biodistribution of the two SSIs was seen, adhering to their site-specific targeting. QBKPN appeared to migrate from the site of injection (abdomen) to the cervical lymph nodes which are nearer to the respiratory tract and lungs. QBECO remained in the abdominal region, with lymphatic trafficking to the inguinal lymph nodes, which are nearer to GI-proximal tissues/organs. Immune infiltration at the site of injection comprised of neutrophils for both SSIs, and macrophages for only QBKPN.
Radiolabeling of SSIs allows for longitudinal in vivo imaging of biodistribution and trafficking. PET imaging revealed differential biodistribution of the SSIs based on the organotropism of the bacteria from which the SSI is derived. Trafficking from the site of injection to the targeted site is in part mediated via the lymphatics and involves macrophages and neutrophils.
靶向特定部位的免疫调节剂（SSIs）是一类新型治疗药物，由失活的细菌物种制成，旨在调节靶向器官的先天免疫系统。QBECO 是一种肠道靶向 SSI，正在临床推进以治疗和/或预防炎症性肠病、癌症和胃肠道（GI）和近端器官的严重感染，而 QBKPN 是一种肺部靶向 SSI，正在临床开发用于治疗和/或预防慢性炎症性肺病、肺癌和呼吸道感染。虽然这些 SSI 在临床前和临床研究中已证明具有安全性和概念验证，但它们的转运和生物分布的详细了解尚未完全确定。
用 [Zr] 标记 QBECO 和 QBKPN，并皮下注射到健康小鼠中。 这些小鼠每天进行正电子发射断层扫描（PET）成像，持续八天，以追踪 SSI 的生物分布。 从注射部位采集组织，并进行免疫组织化学探测以检测免疫细胞浸润。
两种 SSI 的生物分布存在差异，这与其靶向特定部位的特性相符。 QBKPN 似乎从注射部位（腹部）迁移到更接近呼吸道和肺部的颈部淋巴结。 QBECO 留在腹部区域，通过淋巴系统迁移到更接近 GI 近端组织/器官的腹股沟淋巴结。 注射部位的免疫浸润包括两种 SSI 的中性粒细胞，以及仅 QBKPN 的巨噬细胞。
SSI 的放射性标记允许进行生物分布和转运的纵向体内成像。 PET 成像显示，基于 SSI 衍生细菌的器官亲嗜性，SSI 的生物分布存在差异。从注射部位到靶向部位的转运部分是通过淋巴系统介导的，涉及巨噬细胞和中性粒细胞。
