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:
- 金额:$ 20万
- 依托单位:
- 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:
- 关键词:
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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RAM SASISEKHARAN其他文献
RAM SASISEKHARAN的其他文献
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{{ truncateString('RAM SASISEKHARAN', 18)}}的其他基金
Structure-Function Relationship of Glycosaminoglycans
糖胺聚糖的结构-功能关系
- 批准号:
8821745 - 财政年份:2015
- 资助金额:
$ 20万 - 项目类别:
Structure-Function Relationship of Glycosaminoglycans
糖胺聚糖的结构-功能关系
- 批准号:
9754832 - 财政年份:2015
- 资助金额:
$ 20万 - 项目类别:
Structure-Function Relationship of Glycosaminoglycans
糖胺聚糖的结构-功能关系
- 批准号:
9341332 - 财政年份:2015
- 资助金额:
$ 20万 - 项目类别:
Characterization and Development of a Cross Spectrum Anti-Dengue Antibody
跨谱抗登革热抗体的表征和开发
- 批准号:
9115535 - 财政年份:2014
- 资助金额:
$ 20万 - 项目类别:
Characterization and Development of a Cross Spectrum Anti-Dengue Antibody
跨谱抗登革热抗体的表征和开发
- 批准号:
8692261 - 财政年份:2014
- 资助金额:
$ 20万 - 项目类别:
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
- 批准号:
8881515 - 财政年份:2014
- 资助金额:
$ 20万 - 项目类别:
Characterization and Development of a Cross Spectrum Anti-Dengue Antibody
跨谱抗登革热抗体的表征和开发
- 批准号:
8897260 - 财政年份:2014
- 资助金额:
$ 20万 - 项目类别:
Investigating Complex Glycans on Biological Surfaces
研究生物表面上的复杂聚糖
- 批准号:
8072127 - 财政年份:2010
- 资助金额:
$ 20万 - 项目类别:
Investigating Complex Glycans on Biological Surfaces
研究生物表面上的复杂聚糖
- 批准号:
7962684 - 财政年份:2010
- 资助金额:
$ 20万 - 项目类别:
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