IMMUNOPHARMACOTHERAPY AS A TREATMENT FOR COCAINE ABUSE

免疫药物治疗可卡因滥用

基本信息

批准号：
2121156
负责人：
Kim Janda
金额：
$ 23.83万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-01-01 至 1996-12-31
项目状态：
已结题

项目摘要

Cocaine abuse is among the most pressing health/sociological problems confronting developed nations the world over. In the U.S., thousands of new users are added each day and each year a large proportion die from overdose or other toxic influences. The effects on the unborn can be especially tragic. Yet, it is those people addicted to cocaine that represent the financial and social deterioration which this drug can inflict, Significantly, its abuse becomes elevated from the level of the individual as the addict effects not only his own well-being but the health of others and infrastructure of society. Of particular concern is the link between intravenous cocaine administration and the spread of AIDS. At present, there is no concrete medical solution to the cocaine problem. Unlike some other drugs of abuse, there is no pharmacotherapy considered to be of value. The biochemistry of action of cocaine is complex having perhaps the most unique and powerful reinforcing properties of any drug. While a number of potential antagonists, agonists, and anti- depressants have been explored, it has become obvious that alternatives are necessary. One approach might rely on immunological tacts. Such a strategy provides an opportunity to develop pharmacological agents for direct treatment of acute cocaine toxicity and as medications for rehabilitation or preventative purposes. In this way, social programs would be bolstered by an objective scientific foundation. Most exciting, immunological protocols offer the possibility of abating cocaine abuse through vaccine designs. This proposal delineates such an immunopharmacological program. One aspect focuses on monoclonal antibody (mAb) technology derived from both hybridoma and combinatorial library protocols. This encompasses the generation of antibodies which bind cocaine with high affinity and specificity, catalytic antibodies to cleave the benzoyl ester of cocaine, and the elicitation of anti-idiotypes which bear the internal-image of cocaine. The synthesis of new compounds for use as haptens and in ELISA protocols are described. Further, the immunochemistry used for mAb production is applicable to vaccine development via immunoconjugates and anti-idiotypes. The treatment of cocaine toxicity with mAbs and the protection from the effects of cocaine through vaccination will be studied using rat behavioral paradigms. Another feature in the plan is the implementation of molecular biological techniques to alter the structure-function of mAbs. These will be used to enhance mAb binding affinity or introduce catalytic activity. The molecular biology used in the phage-display systems for obtaining mAbs is outlined. In this regard, ground-breaking research has led to the development of synthetic human mAb combinatorial libraries.

可卡因滥用是最紧迫的健康/社会问题之一与世界发达国家对抗。在美国，成千上万每天都会增加新用户，每年都有很大一部分用户死于此服用过量或其他毒性影响。对胎儿的影响可能是特别悲惨。然而，正是那些对可卡因上瘾的人代表了这种药物可能导致的经济和社会恶化值得注意的是，其滥用程度已从作为瘾君子的个人不仅影响他自己的福祉，而且影响他人的健康和社会基础设施。特别值得关注的是静脉注射可卡因与传播可卡因之间的联系艾滋病。目前，还没有针对可卡因的具体医疗解决方案问题。与其他一些滥用药物不同，没有药物疗法被认为是有价值的。可卡因作用的生物化学是复合物可能具有最独特和最强大的增强性能任何药物。虽然许多潜在的拮抗剂、激动剂和抗抑制剂已经被探索过，很明显替代品是必要的。一种方法可能依赖于免疫策略。这样一个战略提供了开发药物制剂的机会直接治疗急性可卡因中毒并作为药物治疗康复或预防目的。这样，社会项目将会得到客观的科学基础的支持。最令人兴奋的是，免疫学方案提供了减少可卡因滥用的可能性通过疫苗设计。该提案描绘了这样一个免疫药理学计划。一方面关注单克隆抗体来自杂交瘤和组合文库的 (mAb) 技术协议。这包括产生结合的抗体可卡因具有高亲和力和特异性，催化抗体裂解可卡因的苯甲酰酯，以及抗独特型的引发具有可卡因的内部形象。新用途化合物的合成如半抗原和 ELISA 方案中所述。此外，用于单克隆抗体生产的免疫化学适用于疫苗通过免疫偶联物和抗独特型进行开发。治疗 mAb 的可卡因毒性以及免受可卡因影响的保护将使用大鼠行为范式来研究通过疫苗接种的情况。该计划的另一个特点是分子生物学的实施改变单克隆抗体结构功能的技术。这些将用于增强 mAb 结合亲和力或引入催化活性。这用于获得单克隆抗体的噬菌体展示系统中使用的分子生物学是概述。在这方面，突破性的研究导致了合成人单克隆抗体组合文库的开发。