Varkony Haim, Weinstein Vera, Klinger Ety, Sterling Jeffrey, Cooperman Helena, Komlosh Turi, Ladkani David, Schwartz Rivka
Innovative R&D Division TEVA Pharmaceutical Industries, Netanya, Israel.
Expert Opin Pharmacother. 2009 Mar;10(4):657-68. doi: 10.1517/14656560902802877.
Glatiramer acetate (GA) is a complex heterogenous mixture of polypeptides with immunomodulatory activity approved for treatment of relapsing-remitting multiple sclerosis. GA is the first, and was until recently, the only member of the glatiramoids, a family of synthetic copolymer mixtures comprising the four amino acids, L-glutamic acid, L-alanine, L-lysine and L-tyrosine, in a defined molar ratio. Another glatiramoid, protiramer, was recently evaluated in preclinical studies and in two small Phase II clinical trials with relapsing-remitting multiple sclerosis patients. Due to the complexity and heterogeneity of GA and other glatiramoids, the clinically active epitopes within the mixture cannot be identified and the consistency of polypeptide sequences within the mixture is dependent on a tightly controlled manufacturing process. Although no two glatiramoids can be proved identical, it is possible to differentiate among members of the glatiramoid class using analytical methods and immunological and biological markers. Even slight differences in the distribution of molecular masses or in the composition of antigenic polypeptide sequences among glatiramoids can significantly influence their efficacy, toxicity and immunogenicity profiles. Experience with GA may be instructive regarding important safety and efficacy considerations for new glatiramoid mixtures now in development.
醋酸格拉替雷（GA）是一种具有免疫调节活性的多肽复杂异质混合物，已被批准用于治疗复发缓解型多发性硬化症。GA是合成共聚物混合物家族（称为格拉替雷类）中的首个成员，直到最近仍是唯一成员，该家族由L-谷氨酸、L-丙氨酸、L-赖氨酸和L-酪氨酸这四种氨基酸按特定摩尔比组成。另一种格拉替雷protiramer最近在临床前研究以及两项针对复发缓解型多发性硬化症患者的小型II期临床试验中进行了评估。由于GA和其他格拉替雷的复杂性和异质性，混合物中的临床活性表位无法确定，混合物中多肽序列的一致性取决于严格控制的生产过程。尽管无法证明两种格拉替雷完全相同，但可以使用分析方法以及免疫和生物学标记物来区分格拉替雷类成员。格拉替雷类之间分子量分布或抗原多肽序列组成的细微差异都可能显著影响其疗效、毒性和免疫原性特征。GA的经验可能为目前正在研发的新型格拉替雷混合物的重要安全性和有效性考量提供指导。
