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DIGOXIN-SPECIFIC HUMAN ANTIBODIES FROM TRANSGENIC MICE

来自转基因小鼠的地高辛特异性人类抗体

基本信息

批准号：
2030331
负责人：
William James Ball
金额：
$ 10万
依托单位：
MEDAREX, INC.
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-15 至 1998-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2030331
关键词：
digoxin drug adverse effect drug design /synthesis /production genetically modified animals immunotherapy laboratory mouse monoclonal antibody overdose

项目摘要

The long-term goal of this project is to develop human monoclonal antibodies directed against the cardiac glycosides, digoxin and digitoxin,that can be used as therapeutic agents in the treatment of toxic overdoses of these drugs. The generated antibodies would be of considerable value because these two drugs are among the most commonly prescribed drugs in the US, yet have a very narrow margin of safety between their beneficial and their toxic effects. Currently only an Fab fragment preparation of heterogeneous sheep antibodies is available and their use is limited because of their nonhuman origin and variable binding characteristics. In this proposal, we plan to utilize GenPharm International's recent achievements in using transgene technology to develop a mice strain that produces both human IgM and IgG immunoglobulins. These mice have been shown to respond to immunizations with both primary and secondary immune responses. Therefore we will use digoxin- and digitoxin-ovalbumin conjugates to provoke the generation of human IgG anti-digitalis antibodies. Standard hybridoma technology will be used to produce, identify and clone hybridoma cells secreting high affinity, human anti-drug monoclonal antibodies. The binding affinities and specificities of these monclonal antibodies will be fully characterized and those most suitable for Phase II development as clinically useful agents will be identified. PROPOSED COMMERCIAL APPLICATION: The cardiac glycosides are among the most commonly prescribed drugs in the US. It is estimated that 13% of our population over 65 receive treatment with them and that 4-6% of all patients admitted to the hospital for apparent heart failure are suffering from toxic overdoses of these drugs.While most of these patients do not require administration of the sheep anti-digoxin Fab fragments, it is estimated that currently about 2,500 patients/year in the US undergo such treatment. A human monoclonal antibody should not only replace the present product but be a much safer and more widely used clinical agent.

该项目的长期目标是开发人类单克隆