Integrated approach to determine equivalence in complex drug mixtures

确定复杂药物混合物等效性的综合方法

基本信息

批准号：
8925805
负责人：
RAM SASISEKHARAN
金额：
$ 20万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925805
关键词：
Integrated approach determine equivalence complex

项目摘要

PROJECT SUMMARY Heterogeneity and complexity of biopharmaceutical agents developed over the past decade or so can be defined at two levels. First, in the case of protein systems such as monoclonal antibodies, the primary source of heterogeneity arises from glycosylation post‐translational modifications mainly at the conserved N‐linked glycosylation sites in the constant (Fc) region of the heavy chain. The Fc glycosylation plays a role in maintaining antibody stability and also contributes to binding with Fc gamma receptor isoforms that in turn mediate effector functions such as antibody dependent cellular cytotoxicity (ADCC). Second, in the case of complex drugs such as heparin or low molecular weight heparin (LMWH) etc. the main component of the drug is a heterogeneous mixture of linear (in the case of heparin) or branched glycan polymers with a molecular weight and anionic charge distribution. Developing follow‐on (or generic) versions of such complex biopharmaceutical mixtures is therefore in constant need for new technologies to define and characterize these mixtures as comprehensively as possible from the standpoint of chemical and biological equivalence. Despite these advances, there remain gaps in linking glycosylation heterogeneity with antibody efficacy and adverse effects such as those related to host immune response to a human antibody generated in a non‐human cell line. In the case of complex glycan drugs such as heparin and LMWH, there is a larger gap in linking mixture properties with biological action of the drug. For example, despite the fact that heparin has been quality controlled and used in clinic for several decades, a serious global health crisis associated with administration of heparin emerged in early March 2008 which was later identified by us and others to be associated with an unnatural glycosaminoglycan contaminant species. We have extensive experience in characterizing complex biopharmaceutical mixtures in terms of their structural attributes and how these attributes impinge on their function. A central component of our approach is the ability to employ a computational framework that we had built over the past decade or so in integrating diverse datasets pertaining to complex glycan mixtures. This framework permitted us to incorporate orthogonal datasets including analytical and functional data to get to the bottom of structure‐function relationships of complex glycan mixtures. In this proposal we seek to build on this computational platform and our extensive experience to build a robust set of integrated tools and algorithms to determine the extent of characterization required for establishing equivalence for therapeutics that are used in the clinic. Through the studies proposed here, we believe that we will make a contribution towards determining criteria for sufficiency in characterization of complex therapeutic agents in establishing equivalence.

项目概要可以定义过去十年左右开发的生物药剂的异质性和复杂性首先，对于单克隆抗体等蛋白质系统来说，这是异质性的主要来源。产生于糖基化翻译后修饰，主要发生在保守的 N-连接糖基化位点重链恒定 (Fc) 区 Fc 糖基化在维持抗体稳定性方面发挥着作用。有助于与 Fc gamma 受体亚型结合，进而介导抗体等效应功能其次，对于肝素或低分子量等复杂药物而言。肝素（LMWH）等。该药物的主要成分是线性（肝素）或具有分子量和阴离子电荷分布的支链聚糖聚合物。因此，这种复杂的生物制药混合物的版本不断需要新技术来定义和从化学和生物等效性的角度尽可能全面地表征这些混合物。尽管取得了这些进展，但在将糖基化异质性与抗体功效和抗体功效联系起来方面仍然存在差距。副作用，例如与宿主对非人类细胞系中产生的人类抗体的免疫反应相关的副作用。对于肝素和 LMWH 等复杂聚糖药物，在将混合物特性与药物的生物作用。例如，尽管肝素已经过质量控制并在临床中使用几十年来，2008 年 3 月上旬出现了与肝素管理相关的严重全球健康危机后来我们和其他人发现它与非天然糖胺聚糖污染物种类有关。我们在表征复杂生物制药混合物的结构方面拥有丰富的经验属性以及这些属性如何影响其功能。我们方法的核心组成部分是能够采用我们在过去十年左右建立的计算框架来整合不同的数据集该框架允许我们合并正交数据集，包括分析和功能数据，以深入了解复杂聚糖混合物的结构-功能关系。我们寻求建立在这个计算平台和我们丰富的经验基础上的建议，以建立一套强大的集成工具和算法，以确定建立等效性所需的表征程度通过这里提出的研究，我们相信我们将做出贡献。确定复杂治疗剂表征充分性的标准等价。