Antibody engineering: targeting Bacillus anthracis

炭疽杆菌构成了巨大的生物恐怖主义威胁。尽管抗生素可以有效地治疗 在治疗炭疽感染时，早期诊断至关重要。此外，具有抗生素耐药性的菌株有 已经被开发出来了。也有人担心现有疫苗的有效性和安全性，以及 为新生儿接种疫苗会加剧安全问题。被动免疫疗法 抗体将提供一种有吸引力的替代保护途径，这将是有效的 对抗抗生素耐药菌株。然而，合适的(人源化)抗体目前还不是 可用。在预防中使用被动抗体也需要频繁的剂量，因为 现有抗体的血清半衰期有限。我们将努力克服这些缺点。 首先，我们计划使用目前的抗体工程方法来产生针对 炭疽杆菌的孢子和毒素成分。第二，我们将使用已经被 我们实验室开发的延长丙种球蛋白(IgG)血清半衰期的药物。我们有 表明通过改造抗体的位置来增加血清持久性是可能的 它与Fc受体FcRN相互作用。这种Fc受体还调节免疫球蛋白的转移。 穿过母胎屏障。因此，血清半衰期增加的抗体很可能 将通过增加与FcRN的结合而更有效地转移到胎儿体内。我们的具体目标是： 1)产生有效的抗保护性抗原和抗孢子壳蛋白抗体；2) 增加抗体的血清半衰期；3)分析保护性抗体的转移 跨越人类和小鼠母胎屏障；4)使最有希望的抗体人性化 在进一步研究中使用。建议的分析应为 炭疽病的预防和治疗。他们还应该为理解这一角色提供新的见解 抗体在限制感染方面的作用，这与其他病原体具有更广泛的相关性。

Bacillus anthracis poses an enormous bioterrorism threat. Although antibiotics can be effective in treating anthrax infection, early diagnosis is essential. In addition, antibiotic resistant strains have been developed. There is also concern about the efficacy and safety of existing vaccines, and safety issues are exacerbated for the vaccination of neonates. Passive immunotherapy with antibodies would provide an attractive, alternative route for protection which would be effective against antibiotic resistant strains. However, suitable (humanized) antibodies are currently not available. The use of passive antibodies in prophylaxis also necessitates frequent doses due to the limited serum half-life of existing antibodies. We will attempt to overcome these shortcomings. First, we plan to use current methods of antibody engineering to generate antibodies that target both spore and toxin components of B. anthracis. Second, we will use technology that has been developed in our laboratory to increase the serum half-life of gammaglobulins (IgGs). We have shown that it is possible to increase the serum persistence by engineering the site of an antibody which interacts with the Fc receptor, FcRn. This Fc receptor also regulates the transfer of IgG across the maternofetal barrier. It is therefore likely that antibodies with increased serum half-lives will be transferred more efficiently to the fetus via increased binding to FcRn. Our specific aims are: 1) to generate effective anti-protective antigen and anti-spore coat protein antibodies; 2) to increase the serum half-lives of the antibodies; 3) to analyze the transfer of protective antibodies across human and murine maternofetal barriers; 4) to humanize the most promising antibodies for use in further studies. The proposed analyses should provide effective reagents for the prophylaxis and treatment of anthrax. They should also give new insight into understanding the role of antibodies in limiting infection, and this has broader relevance to other pathogens.