NHLBI MAINTENANCE OF CANINE MODELS OF HUMAN BLEEDING DISORDERS- TASK AREA B CORE SCIENTIFIC PROJECT TO DEVELOP A BISPECIFIC MONOCLONAL ANTIBODY

本项目的目标是开发一种双功能单抗，它将结合犬类凝血固定蛋白和FX，用于预防血友病A犬在具有和不具有犬类FVIII抑制抗体的情况下出血。这种双功能单抗将通过修改目前在犬血浆中不起作用的人类产品(emicizumab或hemLibra™)来制造。UNC的任务顺序提案代表了开发一种双功能单抗的临床意义工作，该单抗将结合犬凝血FIX和FX，以防止血友病A犬在有和没有针对犬FVIII的抑制性抗体的情况下出血。这种抗体的研制将极大地提高使用抑制剂的血友病A犬的存活率，从而为抑制物的形成、预防和消融提供研究。它还将提供一个急需的动物模型系统，用于研究在人类中使用emicizumab时发生的不完全了解的血栓并发症，并解决自FDA批准药物以来出现的一系列临床问题。该提案包括里程碑和具有明确成功标准的时间表。北卡罗来纳大学的场地环境很好，团队经验丰富。提供了明确的时间表、里程碑和既定程序。

The goal of this TO is to develop a bispecific monoclonal antibody that will bind canine coagulation FIX and FX for preventing bleeding in hemophilia A dogs with and without inhibitory antibodies to canine FVIII. This bispecific monoclonal antibody will be made by modifying the human product (emicizumab or HemLibra™) that currently does not work in canine plasma. The task order proposal from the UNC represents clinically significant work to develop a bispecific monoclonal antibody that will bind canine coagulation FIX and FX for preventing bleeding in hemophilia A dogs with and without inhibitory antibodies to canine FVIII. The development of this antibody will enable studies of inhibitor formation, prevention and ablation by greatly increasing the survival rate of hemophilia A dogs with inhibitors. It will also provide a critically needed animal model system for investigating incompletely understood thrombotic complications that have occurred with emicizumab use in humans and for addressing a series of clinical questions that have arisen since the FDA granted drug approval. The proposal includes milestones and a timeline with defined success criteria. The UNC site has an excellent environment and the team is experienced. Clear timelines, milestones and established procedures are provided.