Generation of a Monoclonal Antibody Agonist to Toll-Like Receptor 5

描述(由申请人提供)：细菌鞭毛蛋白是一种Toll样受体5(TLR5)激动剂，通过激活核因子-(B(NF-(B)提供对高剂量辐射的保护。核因子-B信号可诱导多种促进细胞存活和组织再生的因子，包括细胞凋亡抑制物、活性氧清除剂和细胞因子。我们已经设计出CBLB502，一种免疫原性降低的优化鞭毛蛋白衍生物，用于开发辐射防护剂。虽然CBLB502目前处于生物防御应用的第一阶段试验，但预计它也将有广泛的医疗应用，包括减少抗癌放射和化疗的不良副作用。然而，反复给予CBLB502可能会诱导中和免疫反应，从而限制其有效性。为了开发免疫原性降低的替代TLR5激动剂，我们产生了抗人TLR5的单抗，在结合时激活TLR5。这项建议侧重于产生的激动型抗体的详细功能和免疫化学特征，以便选择最有效和最特异地激活人类来源的上皮细胞和单核细胞中的TLR5的候选者，并激活临床前药物评价中常用的其他物种的TLR5。在该项目的下一阶段，将在体内评估选定的抗体的辐射防护效果。 公共卫生相关性：用细菌鞭毛蛋白的衍生物CBLB502药理激活TLR5是保护敏感组织免受急性辐射暴露和其他类型应激的有效方法。然而，CBLB502的某些医学应用(如抗癌放射治疗期间保护正常组织)的延长治疗可能会引起不良免疫反应。免疫原性降低的替代TLR5激动剂，例如本提案的主题激动型抗体，将是此类应用的理想药物，可能会导致临床影响，如改善放射治疗的治疗指数。

DESCRIPTION (provided by applicant): Systemic treatment with the bacterial flagellin protein, a Toll-like receptor 5 (TLR5) agonist, provides protection against high dose radiation through activation of nuclear factor-(B (NF-(B). NF-(B signaling induces multiple factors that contribute to cell survival and tissue regeneration, including apoptosis inhibitors, reactive oxygen species scavengers, and cytokines. We have engineered CBLB502, an optimized flagellin derivative with reduced immunogenicity, for development as a radioprotectant. While CBLB502 is currently in Phase 1 trials for biodefense applications, it is also expected to have a wide range of medical applications, including reduction of the adverse side effects of anti-cancer radio- and chemotherapy. However, repeated administration of CBLB502 could induce a neutralizing immune response that would limit its effectiveness. To develop alternative TLR5 agonists with reduced immunogenicity, we generated monoclonal anti-human-TLR5 antibodies that activate TLR5 upon binding. This proposal is focused on detailed functional and immunochemical characterization of the generated agonistic antibodies in order to select the candidates that most potently and specifically activate TLR5 in both epithelial and monocytic cells of human origin and also activate TLR5 from other species commonly used in pre-clinical drug evaluation. In the next phase of the project, the selected antibodies will be evaluated for radioprotective efficacy in vivo. PUBLIC HEALTH RELEVANCE: Pharmacological activation of TLR5 with CBLB502, a derivative of the bacterial flagellin protein, is a powerful approach to protection of sensitive tissues from acute radiation exposure and other types of stress. However, prolonged treatment with CBLB502 for some medical applications (such as protection of normal tissues during anti-cancer radiotherapy) could induce undesirable immune responses. Alternative TLR5 agonists with reduced immunogenicity, such as the agonistic antibodies that are the subject of this proposal, would be ideal drugs for such applications, potentially leading to clinical impacts such as improvement of the therapeutic index of radiation therapy