Fully human recombinant therapeutic anti-vaccinia virus polyclonal antibody

说明(申请人提供)：生物恐怖主义的威胁使天花再次成为对公共健康的潜在威胁，因此需要新的治疗方法或预防措施。在全球疫苗接种计划期间使用的天花疫苗与罕见但严重的不良反应有关，其中一些是致命的，从而阻止了大规模接种。本申请描述了用于预防或治疗天花和相关正痘病毒的重组人多克隆天花抗体的临床前开发。一种特定和有效的抗正痘病毒多克隆抗体将使预防天花成为可能，取代血源性牛痘免疫球蛋白(VIG)，显著改善安全状况和产品供应，减少注射量，并简化注射途径，包括为医护人员和士兵开发可自我管理的注射装置。这种重组多克隆抗体产品将反映自然人类免疫反应的多样性、亲和力和特异性。由于多克隆抗体是针对多个表位和蛋白质的，因此抗体有望具有很高的效力。本项目的总体目标是实现IND的备案。将在GMP下产生一个多克隆主细胞系，并从遗传稳定性和不育性方面进行验证。该电池线将用于生产工艺的开发和扩大。将建立抗体纯化、配方和填充-整理的下游工艺。生产治疗性多克隆抗体的过程和程序已经在Symphogen的更先进的项目中建立，可以进行调整。该多克隆抗体的生物活性将在痘苗病损尾鼠模型和致死小鼠模型中进行测试。如果最初的模型显示出有效性，那么在研究与天花病毒蛋白结合的同时，还将在复制模型中测试其对猴痘病毒的抗病毒活性。综合起来，这些数据可能提供证据，证明多克隆抗体对正痘病毒具有治疗和预防活性。从概念验证研究以及生产和提纯过程中收集的结果将使IND得以填充。

DESCRIPTION (provided by applicant): The threat of bioterrorism has reintroduced smallpox as a potential threat to public health and thereby established a need for novel treatments or prophylactic measures. The smallpox vaccine used during the worldwide vaccination program is associated with rare but serious adverse reactions, some fatal, thereby preventing mass vaccination. This application describes the pre-clinical development of a recombinant human polyclonal smallpox antibody to be used as a prophylactic or therapeutic agent against smallpox, and related orthopoxviruses. A specific and potent anti-orthopoxvirus polyclonal antibody will, enable countermeasure against smallpox, substitute the blood-derived vaccinia immunoglobulin (VIG), providing a significantly improved safety profile and product supply, decreased injection volumes, and easier route of injection, including the development of self-manageable injection devices for health care personnel and soldiers. This recombinant polyclonal antibody product will mirror the diversity, affinity and specificity of the natural human immune response. Because the polyclonal antibody is directed against multiple epitopes and proteins, the antibody is expected to be highly potent. The overall goal of the present project is to enable the filing of an IND. A polyclonal master cell line will be generated under GMP and validated with respect to genetic stability and sterility. The cell line will be used during development of a production process and scale-up. A downstream process for antibody purification, formulation, and fill-finish will be established. Processes and procedures already established in more advanced projects at Symphogen for production of therapeutic polyclonal antibodies can be adapted. The biological activity of the polyclonal antibody will be tested in the vaccinia lesion tail mouse model and a lethal mouse model. If the initial models show efficacy, the antiviral activity will also be assayed against monkeypox virus in a replication model in parallel with studies of binding to variola virus proteins. Combined, the data may provide evidence that the polyclonal antibody exerts both therapeutic and prophylactic activity against orthopoxviruses. The collected results from the proof of concept studies and production and purification processes will enable the filling of an IND.