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

描述（由申请方提供）：使用细菌鞭毛蛋白（一种Toll样受体5（TLR 5）激动剂）进行全身治疗，通过激活核因子-（B）（NF-（B））提供对高剂量辐射的保护。NF-β B信号传导诱导多种有助于细胞存活和组织再生的因子，包括凋亡抑制剂、活性氧清除剂和细胞因子。我们已经设计了CBLB 502，一种优化的鞭毛蛋白衍生物，具有降低的免疫原性，作为一种辐射防护剂的发展。虽然CBLB 502目前正处于生物防御应用的1期试验中，但预计它也将具有广泛的医疗应用，包括减少抗癌放疗和化疗的不良副作用。然而，CBLB 502的重复给药可能诱导中和免疫应答，这将限制其有效性。为了开发具有降低的免疫原性的替代性TLR 5激动剂，我们产生了在结合时激活TLR 5的单克隆抗人TLR 5抗体。该提案集中于所产生的激动性抗体的详细功能和免疫化学表征，以选择最有效和特异性地激活人源上皮细胞和单核细胞中的TLR 5的候选物，并且还激活临床前药物评价中常用的其他物种的TLR 5。在该项目的下一阶段，将评估所选抗体的体内辐射防护功效。 公共卫生相关性：用CBLB 502（细菌鞭毛蛋白的衍生物）药理学活化TLR 5是保护敏感组织免受急性辐射暴露和其他类型的应激的有力方法。然而，CBLB 502在某些医学应用中的长期治疗（如在抗癌放射治疗期间保护正常组织）可能会诱导不良的免疫反应。具有降低的免疫原性的替代性TLR 5激动剂，例如作为该提议的主题的激动性抗体，将是用于此类应用的理想药物，潜在地导致临床影响，例如放射治疗的治疗指数的改善

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