Novel Approach for Fast and Economic Manufacturing of Human Antibodies

描述（由申请人提供）：越来越多的潜在的本地和工程生物威胁剂有效地限制了通过接种疫苗对公众健康的主动保护。另一种方法依赖于使用相应的保护性抗体，这些抗体是预先制成的，作为可注射药物，在反应而不是主动模式下使用。然而，这种方法的实施是复杂的，因为非人类抗体的施用可能引发不良反应的发展。迄今为止，获得足够数量的人类抗体一直是一项具有挑战性的任务。此外，生产抗体的传统方法取决于是否存在相应的疫苗，不能用于权宜之计开发针对新出现感染的保护剂。为了克服这些障碍，我们建议开发一种新的系统来组装和生产人/人嵌合抗体。这种抗体的产生成本是多克隆抗体的一小部分，而且比传统单克隆抗体的时间要短得多，同时仍然保持人类的本性。总的来说，我们的系统将比杂交瘤技术更安全。此外，它还可用于在出现新威胁物的最初迹象时发展保护性实体。

DESCRIPTION (provided by applicant): A growing number of potential native and engineered biothreat agents effectively limit the proactive protection of public health through vaccination. An alternative approach relies on the use of corresponding protective antibodies that are pre-made and are used as injectable drugs in reactive rather than proactive mode. The implementation of this approach, however, is complicated by the fact that administration of non-human antibodies can trigger development of adverse reactions. Securing of human antibodies in sufficient quantities so far has been a challenging task. Also, the traditional approach of producing antibodies depends on the existence of corresponding vaccines and cannot be used for expedient development of protective agents against newly emerging infections. To overcome these hurdles we propose to develop a novel system for assembly and production of human/human chimeric antibodies. Such antibodies can be generated at a fraction of the cost of raising polyclonal antibodies and in substantially shorter times than traditional monoclonal antibodies while still remaining human in nature. In general, our system will be much safer to operate with than hybridoma technology. In addition, it can be used for development of protective entities at the first signs of emergence of new threat agents. Phase I efforts will test the feasibility of our approach by developing human/human chimeras that will recognize botulinum neurotoxin serotype A. To assemble such chimeras, we will introduce a proprietary cloning scheme that reduces the risk of modifying native antigen-recognizing sequences and substantially simplifies the process of assembly of immunoglobulin-encoding sequences. This will make the system suitable for high-throughput format applications. Regulatory elements incorporated into cloning vectors will enable rapid detection of cells producing antibodies of interest and selection of host cells for industrial production, thus increasing the efficiency of the process and decreasing price of the final product. During Phase II, the developed cloning approach and expression vectors will be used to generate IgG variants of chimeric antibodies that will be able to neutralize toxic effects of botulinum neurotoxin serotypes A and B and will be suitable for use as anti-botulinum drugs. The developed enabling technology will be suitable for generating protective antibodies against other biothreat agents. PUBLIC HEALTH RELEVANCE: The current project will provide a new way for development of human anti-pathogen antibodies and opens new opportunities for passive vaccination as a way of protecting humans against infectious diseases and toxins.