Thayer School of Engineering, Dartmouth, Hanover, NH 03755, USA.
Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Sci Adv. 2020 Sep 2;6(36). doi: 10.1126/sciadv.abb9011. Print 2020 Sep.
There is a critical need for novel therapies to treat methicillin-resistant (MRSA) and other drug-resistant pathogens, and lysins are among the vanguard of innovative antibiotics under development. Unfortunately, lysins' own microbial origins can elicit detrimental antidrug antibodies (ADAs) that undermine efficacy and threaten patient safety. To create an enhanced anti-MRSA lysin, a novel variant of lysostaphin was engineered by T cell epitope deletion. This "deimmunized" lysostaphin dampened human T cell activation, mitigated ADA responses in human HLA transgenic mice, and enabled safe and efficacious repeated dosing during a 6-week longitudinal infection study. Furthermore, the deimmunized lysostaphin evaded established anti-wild-type immunity, thereby providing significant anti-MRSA protection for animals that were immune experienced to the wild-type enzyme. Last, the enzyme synergized with daptomycin to clear a stringent model of MRSA endocarditis. By mitigating T cell-driven antidrug immunity, deimmunized lysostaphin may enable safe, repeated dosing to treat refractory MRSA infections.
迫切需要新型疗法来治疗耐甲氧西林金黄色葡萄球菌（MRSA）和其他耐药病原体，而溶菌酶是正在开发的创新抗生素的先锋之一。不幸的是，溶菌酶自身的微生物起源会引发有害的抗药物抗体（ADA），从而降低疗效并威胁患者安全。为了创造一种增强的抗 MRSA 溶菌酶，通过 T 细胞表位缺失工程改造了一种新型的溶葡萄球菌酶变体。这种“脱免疫”的溶葡萄球菌酶减弱了人类 T 细胞的激活，减轻了人类 HLA 转基因小鼠中的 ADA 反应，并能够在 6 周的纵向感染研究中安全有效地重复给药。此外，脱免疫的溶葡萄球菌酶逃避了已建立的针对野生型的免疫，从而为对野生型酶具有免疫经验的动物提供了显著的抗 MRSA 保护。最后，该酶与达托霉素协同作用，清除了严格的 MRSA 心内膜炎模型。通过减轻 T 细胞驱动的抗药物免疫，脱免疫的溶菌酶可能能够安全、重复给药来治疗难治性 MRSA 感染。
