Glatiramer Acetate (GA) is an immunomodulatory medicine approved for the treatment of multiple sclerosis, whose mechanisms of action are yet to be fully elucidated. GA is comprised of a complex mixture of polypeptides with different amino acid sequences and structures. The lack of sensible information about physicochemical characteristics of GA has contributed to its comprehensiveness complexity. Consequently, an unambiguous determination of distinctive attributes that define GA is of highest relevance towards dissecting its identity. Herein we conducted a study of characteristic GA heterogeneities throughout its manufacturing process (process signatures), revealing a strong impact of critical process parameters (CPPs) on the reactivity of amino acid precursors; reaction initiation and polymerization velocities; and peptide solubility, susceptibility to hydrolysis, and size-exclusion properties. Further, distinctive GA heterogeneities were correlated to defined immunological and toxicological profiles, revealing that GA possesses a unique repertoire of active constituents (epitopes) responsible of its immunological responses, whose modification lead to altered profiles. This novel approach established CPPs influence on intact GA peptide mixture, whose physicochemical identity cannot longer rely on reduced properties (based on complete or partial GA degradation), providing advanced knowledge on GA structural and functional relationships to ensure a consistent manufacturing of safe and effective products.

中文翻译：

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醋酸格拉替雷合成中的工艺特征：结构和功能关系。

醋酸格拉替雷（GA）是一种被批准用于治疗多发性硬化症的免疫调节药物，其作用机理尚未完全阐明。GA由具有不同氨基酸序列和结构的多肽的复杂混合物组成。缺乏有关GA的理化特性的明智信息，导致了其全面性的复杂性。因此，确定GA的独特属性的明确确定与剖析其身份具有最高的相关性。本文中，我们对整个生产过程中特征性GA异质性进行了研究（过程特征），揭示了关键过程参数（CPP）对氨基酸前体反应性的强烈影响。反应引发和聚合速度；和肽的溶解度 对水解的敏感性以及尺寸排阻性质。此外，独特的GA异质性与已定义的免疫学和毒理学特征相关，表明GA具有负责其免疫学反应的活性成分（表位）的唯一组成部分，其修饰导致特征改变。这种新颖的方法建立了CPP对完整的GA肽混合物的影响，其物理化学特性不再能够依赖于降低的特性（基于完全或部分的GA降解），从而提供了有关GA结构和功能关系的高级知识，以确保安全有效地生产稳定的产品。揭示了GA具有负责其免疫反应的活性成分（表位）的独特库，其修饰会导致谱图发生变化。这种新颖的方法建立了CPP对完整的GA肽混合物的影响，其物理化学特性不再能够依赖于降低的特性（基于完全或部分的GA降解），从而提供了有关GA结构和功能关系的高级知识，以确保安全有效地生产稳定的产品。揭示了GA具有负责其免疫反应的活性成分（表位）的独特库，其修饰会导致谱图发生变化。这种新颖的方法建立了CPP对完整的GA肽混合物的影响，其物理化学特性不再能够依赖于降低的特性（基于完全或部分的GA降解），从而提供了有关GA结构和功能关系的高级知识，以确保安全有效地生产稳定的产品。