Pfizer, Inc., BioTherapeutics Pharmaceutical Sciences, Pharmaceutical Research and Development, Chesterfield, Missouri 63017, USA.
J Pharm Sci. 2011 Feb;100(2):354-87. doi: 10.1002/jps.22276. Epub 2010 Aug 25.
All protein therapeutics have the potential to be immunogenic. Several factors, including patient characteristics, disease state, and the therapy itself, influence the generation of an immune response. Product-related factors such as the molecule design, the expression system, post-translational modifications, impurities, contaminants, formulation and excipients, container, closure, as well as degradation products are all implicated. However, a critical examination of the available data shows that clear unequivocal evidence for the impact of these latter factors on clinical immunogenicity is lacking. No report could be found that clearly deconvolutes the clinical impact of the product attributes on patient susceptibility. Aggregation carries the greatest concern as a risk factor for immunogenicity, but the impact of aggregates is likely to depend on their structure as well as on the functionality (e.g., immunostimulatory or immunomodulatory) of the therapeutic. Preclinical studies are not yet capable of assessing the clinically relevant immunogenicity potential of these product-related factors. Simply addressing these risk factors as part of product development will not eliminate immunogenicity. Minimization of immunogenicity has to begin at the molecule design stage by reducing or eliminating antigenic epitopes and building in favorable physical and chemical properties.
所有蛋白质治疗药物都有潜在的免疫原性。一些因素，包括患者特征、疾病状态和治疗本身，会影响免疫反应的产生。产品相关因素，如分子设计、表达系统、翻译后修饰、杂质、污染物、配方和赋形剂、容器、封口以及降解产物等，都与之相关。然而，对现有数据的仔细审查表明，缺乏明确的证据表明这些因素会对临床免疫原性产生影响。没有报告能够明确解析产品属性对患者易感性的临床影响。聚集是免疫原性的一个最大风险因素，但聚集物的影响可能取决于其结构以及治疗药物的功能（例如免疫刺激性或免疫调节性）。临床前研究尚不能评估这些产品相关因素的临床相关免疫原性潜力。在产品开发过程中简单地解决这些风险因素并不能消除免疫原性。通过减少或消除抗原表位并构建有利的物理和化学性质，必须从分子设计阶段开始将免疫原性最小化。
