Antibody engineering: targeting Bacillus anthracis

超出所提供的空间。炭疽芽孢杆菌构成了巨大的生物恐怖主义威胁。虽然抗生素可以有效治疗炭疽感染，但早期诊断是至关重要的。此外，已经开发出耐抗生素菌株。人们还对现有疫苗的有效性和安全性表示关切，对新生儿接种疫苗的安全性问题更加严重。用抗体进行被动免疫治疗将提供一种有吸引力的、可替代的保护途径，可以有效地对抗抗生素耐药菌株。然而，目前还没有合适的（人源化的）抗体。由于现有抗体的血清半衰期有限，在预防中使用被动抗体也需要经常给药。我们将努力克服这些缺点。首先，我们计划利用现有的抗体工程方法来产生针对炭疽芽孢杆菌孢子和毒素成分的抗体。其次，我们将使用我们实验室开发的技术来延长血清中γ球蛋白（igg）的半衰期。我们已经证明，通过改造与Fc受体（FcRn）相互作用的抗体位点来增加血清持久性是可能的。这种Fc受体也调节IgG通过母胎屏障的转移。因此，血清半衰期增加的抗体可能会通过增加与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)生成有效的抗保护性抗原和抗孢子外壳（外孢子）蛋白抗体；2)增加抗体的血清半衰期；3)使最有希望用于进一步研究的候选物人性化；4)分析保护性抗体跨越人和鼠母胎屏障的转移。所提出的分析应为预防和治疗炭疽提供有效的试剂。它们还应该为理解抗体在限制感染中的作用提供新的见解，这与其他病原体具有更广泛的相关性。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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 (exosporium) protein antibodies; 2) to increase the serum half-lives of the antibodies; 3) to humanize the most promising candidates for use in further studies; 4) to analyze the transfer of protective antibodies across human and murine maternofetal barriers. 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. PERFORMANCE SITE ========================================Section End===========================================