Design and Development of Immunotolerant S. aureus Biotherapies

免疫耐受金黄色葡萄球菌生物疗法的设计和开发

• 批准号: 9253183
• 负责人: Chris Bailey-Kellogg
• 金额: $ 86.85万
• 依托单位: LYTICON, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253183
• 关键词: Achievement; Acute; Address; Anabolism; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antibodies; Bacteremia; Bacteria; Bacterial Infections; Bacterial Proteins; Bacteriophages; Biological; Biological Assay; Biological Response Modifier Therapy; Cause of Death; Cell Wall; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Communities; Complex; Contracts; Cytolysis; Dangerousness; Data; Development; Dose; Drug Costs; Drug Kinetics; Drug resistance; Endocarditis; Engineering; Enzymes; Evolution; Exhibits; Eye Infections; FDA approved; FarGo; Funding; Future; Genetic Engineering; Genus staphylococcus; Goals; Grant; Health; Hospitals; Human; Immune response; Immunoassay; In Vitro; Incidence; Infection; Infectious Skin Diseases; Life; Lung; Lysostaphin; LytA enzyme; Manufactured Materials; Manufacturer Name; Maximum Tolerated Dose; Measures; Methicillin Resistance; Microbial Biofilms; Modeling; Multi-Drug Resistance; Mus; Nature; Oryctolagus cuniculus; Osteomyelitis; Outcome; Patients; Peptidoglycan; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Pichia; Plasma; Positioning Attribute; Predisposition; Process; Production; Public Health; Quality Control; Race; Resistance; Risk; Running; Safety; Sampling; Scientist; Sepsis; Skin; Small Business Technology Transfer Research; Standardization; Staphylococcus aureus; Structure; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Mice; Treatment Efficacy; Validation; Vancomycin-resistant S. aureus; Variant; arm; bacterial resistance; base; chemotherapy; clinical efficacy; clinical translation; community setting; design; design and construction; drug candidate; drug resistant bacteria; efficacy study; endolysin; experimental analysis; humanized mouse; immunogenic; immunogenicity; improved; in vivo; innovation; killings; methicillin resistant Staphylococcus aureus; microbiome; mouse model; multidisciplinary; novel therapeutics; pathogen; pre-clinical; programs; resistant strain; scale up; skin lesion; stem; synergism; therapeutic candidate

The increasing incidence of multi-drug resistance in Staphylococcus aureus and other bacteria represents a public health crisis. Two thirds of hospital-associated S. aureus infections and ~50% of those acquired in the community are now methicillin-resistant (MRSA). MRSA causes >450,000 infections in the US each year, and it is responsible for half of all US deaths caused by drug-resistant bacteria. This threat to public health is creating demand for new therapeutic agents, but traditional antibiotic development pipelines are not keeping pace with the escalating problem. Moreover, antibacterial chemotherapies have proven widely susceptible to rapid evolution of bacterial resistance. Bacteriolytic enzymes, such as Staphylococcus simulans lysostaphin, are an innovative new class of antibiotics that catalytically dismantle cell wall peptidoglycan causing bacterial lysis and death. Due to peptidoglycan’s conserved nature and complex biosynthesis, such enzymes have proven less susceptible to emergent resistance. Unfortunately, lysostaphin elicits anti-drug antibodies in vivo, and this immunogenicity and associated toxicity are barriers to clinical translation. Supported by a successful Phase I STTR grant, Stealth Biologics has re-engineered lysostaphin for reduced immunogenicity in humans. The pivotal outcomes of the Phase I STTR project were: 1) design and construction of F12, a globally deimmunized variant of lysostaphin; 2) in vitro validation of F12’s anti-MRSA potency; 3) preliminary quantification of F12 synergy with FDA approved antibiotics; 4) demonstration of reduced immunogenicity in human cellular immunoassays; and 5) confirmation of reduced in vivo immunogenicity and consequent enhanced therapeutic efficacy in humanized HLA transgenic mice. Collectively, these data suggest that F12 is a promising therapeutic for drug-resistant S. aureus infections. In the proposed Phase II STTR, we have designed a systematic and focused strategy for constructing an F12 target product profile (TPP). In Aim 1, F12 manufacturing and purification will be optimized and scaled up. In Aim 2, an initial clinical indication will be selected based on F12’s in vivo efficacy in two well-established models: rabbit bacteremia/endocarditis and murine skin infection. Efficacy studies will be supported by rigorous experimental analyses of in vitro potency, in vitro resistance susceptibility, in vivo maximum tolerated dose, and in vivo pharmacokinetics. Aim 3 will yield a preliminary toxicity and immunogenicity profile in rabbits and humanized mice that have received escalating single or repeated doses of F12. The resulting data package will enable construction of a TPP that will guide design and execution of comprehensive IND-enabling studies. We anticipate that F12-based antibacterial therapies will prove to be potent, safe, and amenable to repeated dosing. As such, F12 will benefit from competitive advantages relative to more immunogenic phage endolysins, and ultimately it may represent a breakthrough drug for life-threatening MRSA infections.

金黄色葡萄球菌和其他细菌的多重耐药发生率的增加代表了 公共卫生危机。三分之二的医院相关S。金黄色葡萄球菌感染，约50%的人在 社区现在是耐甲氧西林（MRSA）。MRSA每年在美国引起> 450，000例感染， 它是造成美国一半由耐药细菌引起的死亡的原因。对公众健康的威胁是 创造了对新治疗药物的需求，但传统的抗生素开发管道并没有保持 与不断升级的问题同步。此外，抗菌化学疗法已被证明广泛易受 细菌耐药性的快速进化。溶菌酶，如模拟葡萄球菌溶葡萄球菌酶， 是一种创新的新型抗生素，可以催化分解细胞壁肽聚糖， 裂解和死亡。由于肽聚糖的保守性质和复杂的生物合成，这类酶具有 被证明不易受到新出现的抗药性的影响。不幸的是，溶葡萄球菌酶在体内激发抗药抗体， 并且这种免疫原性和相关的毒性是临床转化的障碍。 在成功的I期STTR资助的支持下，Stealth Biologics重新设计了溶葡萄球菌酶， 降低人体免疫原性。第一阶段STTR项目的关键成果是：1）设计和 构建溶葡萄球菌酶的全球去免疫化变体F12; 2）体外验证F12的抗MRSA 效力; 3）初步定量F12与FDA批准的抗生素的协同作用; 4）证明F12与FDA批准的抗生素的协同作用。 在人细胞免疫测定中降低的免疫原性;和5）证实降低的体内免疫原性。 在人源化HLA转基因小鼠中的免疫原性和随后增强的治疗功效。 总的来说，这些数据表明，F12是一个有前途的治疗耐药链球菌。金黄色葡萄球菌感染 在建议的第二阶段短期培训计划中，我们设计了一套有系统和有针对性的策略， F12目标产物谱（TPP）。在目标1中，F12的生产和纯化将得到优化和扩大。 在目标2中，将基于F12在两个已确立的肿瘤中的体内功效来选择初始临床适应症。 模型：兔菌血症/心内膜炎和小鼠皮肤感染。疗效研究将得到严格的支持 体外效力、体外抗性敏感性、体内最大耐受剂量， 和体内药代动力学。目的3将在家兔中产生初步毒性和免疫原性特征， 人源化小鼠已经接受了递增的单次或重复剂量的F12。产生的数据包 将有助于建立一个TPP，以指导设计和执行全面的IND赋能研究。 我们预计，基于F12的抗菌疗法将被证明是有效的，安全的，并可重复使用。 剂量。因此，F12将受益于相对于更具免疫原性的噬菌体内溶素的竞争优势， 最终，它可能成为治疗危及生命的MRSA感染的突破性药物。