Krishnan Rajaraman, Hefti Franz, Tsubery Haim, Lulu Michal, Proschitsky Ming, Fisher Richard
Proclara Biosciences, 222 Third Street, Cambridge, MA 02142, United States.
Curr Alzheimer Res. 2017;14(4):393-402. doi: 10.2174/1567205014666170116152622.
Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies. First, conformational targeting of aggregates of misfolded proteins, rather than less specific binding that includes monomer subunits, which vastly outnumber the toxic targets. Second, since neurodegenerative diseases frequently include more than one potential protein pathology, generic targeting of aggregates by shape might also be a crucial feature of a drug candidate. Incorporating both of these critical features into a viable drug candidate along with high affinity binding has not been achieved with small molecule approaches or with antibody fragments. Monoclonal antibodies developed so far are not broadly acting through conformational recognition. Using GAIM (General Amyloid Interaction Motif) represents a novel approach that incorporates high affinity conformational recognition for multiple protein assemblies, as well as recognition of an array of assemblies along the misfolding pathway between oligomers and fibers. A GAIM-Ig fusion, NPT088, is nearing clinical testing.
针对蛋白质错误折叠途径以及这些途径中中间体毒性的治疗策略主要处于发现和早期开发阶段，除了单克隆抗体外，后者在后期试验中主要未能产生令人信服的临床益处。这些临床失败对未来神经退行性疾病药物开发可能是至关重要的教训。通过采用以下两种策略可能会研发出更有效的药物。第一，针对错误折叠蛋白质聚集体进行构象靶向，而不是针对包含单体亚基的较不特异的结合，单体亚基的数量远远超过有毒靶点。第二，由于神经退行性疾病通常包含不止一种潜在的蛋白质病理学，通过形状对聚集体进行通用靶向也可能是候选药物的一个关键特征。小分子方法或抗体片段尚未将这两个关键特征与高亲和力结合纳入可行的候选药物中。到目前为止开发的单克隆抗体并非通过构象识别广泛发挥作用。使用通用淀粉样蛋白相互作用基序（GAIM）代表了一种新方法，它结合了对多种蛋白质聚集体的高亲和力构象识别，以及对寡聚体和纤维之间错误折叠途径上一系列聚集体的识别。一种GAIM-Ig融合蛋白NPT088已接近临床试验阶段。
