Antipathogen Immunoadhesins

描述（由申请人提供）：多药耐药细菌的兴起，越来越多的侵入性现代医疗实践以及对生物恐怖主义威胁的日益认识，极大地促进了对具有改进药理学和效力的新型抗病原体疗法的追求。在脊椎动物中，病原体产生的保守的非自身分子特征（病原体相关分子模式，PAMPs）被一系列专门的种系编码的可溶性和细胞相关模式识别受体（PRR）识别。我们的目标是使用人工抗体（抗病原体免疫粘附素，APIs）靶向病原体及其产物，该抗体由选定PRR的病原体结合部分和免疫球蛋白的Fc部分组成。PRRs是进化选择来识别广泛的病原体衍生化学物质的，因此我们假设使用单一API，或不同API的组合，可能有助于解决感染。与入侵微生物结合的原料药将为溶解补体系统和Fc受体的组成部分提供额外的锚定位点。这些锚定位点将促进c介导的病原体杀死，增强吞噬作用，因此有助于细菌清除。预计原料药将作为新型病原体-宿主细胞外适配器发挥作用，并有望加速通常需要数周才能发生的反应（产生高度特异性抗体）。本R21申请的目的是探索抗病原体免疫粘附素作为一种新型抗生素/抑菌剂单独使用或与常规抗菌化疗药物联合使用的潜在作用。我们将专注于免疫粘附素的表征和生产，包括c端Fc部分以及TLR2， TLR5, CD14， BPI和因子H作为病原体识别模块。这些分子已经在我们的实验室进行了工程设计，并被证明在a)与纯化的PAMPs结合方面是有价值的。b)与细菌结合（鼠疫耶尔森菌）和c)促进补体介导的杀伤（淋病奈瑟菌）。这种替代性抗菌方法对人类健康的影响是多方面的，最终可能是对传统抗菌化疗的一种有效支持，如果不是一种替代的话，因为有几种细菌菌株对传统抗菌化疗产生了耐药性。原料药可用作预防性制剂（如大手术前）或治疗剂（如败血症期间或暴露于生物战剂后）。这些生物反应调节剂的另一个优点是它们可以中和PAMPs，从而限制促炎细胞因子（IL-1B， TNFa或IL-6）的产生，对失调的无菌和非无菌炎症有直接的有益作用。

DESCRIPTION (provided by applicant): The rise of multidrug resistant bacteria, the increasingly invasive modern medical practices and the increased awareness of the bioterrorist threat, have greatly contributed to the quest for novel anti-pathogen therapies with improved pharmacology and potency. In vertebrates, conserved non self molecular signatures produced by pathogens (pathogen associated molecular patterns, PAMPs) are recognized by a dedicated array of germ line encoded soluble and cell associated pattern recognition receptors (PRR). Our goal is to target pathogens and their products using artificial antibodies (anti-pathogen immunoadhesins, APIs) consisting of the pathogen binding portion of selected PRR and the Fc portion of immunoglobulins. The PRRs were evolutionary selected to recognize a broad spectrum of pathogen derived chemicals, therefore we hypothesize that the use of a single API, or the combination of different ones, may help to resolve infection. APIs which bind to the invading microorganisms will provide additional anchorage sites for both components of the lytic complement system and Fc receptors. These anchorage sites will promote C-mediated pathogen killing, enhance phagocytosis and therefore aid in bacterial clearance. APIs are predicted to function as novel pathogen-host extracellular adapters, and are expected to accelerate responses that normally take weeks to occur (generation of highly specific antibodies). The purpose of this R21 application is to explore a potential role for an arsenal of anti-pathogen immunoadhesins as a novel class of antibiotics/bacteriostatics alone or in combination with conventional antibacterial chemotherapy. We will focus on the characterization and production of immunoadhesins comprising a C-terminal Fc portion along with TLR2, TLR5, CD14, BPI and Factor H as pathogen recognition modules. These molecules have been engineered in our lab and proven to be valuable in a) binding to purified PAMPs. b) binding to bacteria (Yersinia pestis) and c) promoting complement mediated killing (Neisseria gonorrhoeae). The impact on human health of this alternative antibacterial approach is multifold and may eventually represent a valid support, if not an alternative, to conventional antibacterial chemotherapy, for which several bacterial strains acquired resistance. APIs can be useful as prophylactic (e.g. before a major surgery) or therapeutic agents (e.g. during septicemia, or after exposure to a biological warfare agent). An additional advantage of these biologic response modifiers is that they may neutralize PAMPs thus limiting the production of proinflammatory cytokines (IL-1B, TNFa or IL-6) with direct beneficial effects on dysregulated sterile and non sterile inflammatory conditions.