TREATING METABOLIC DISEASES WITH CATALYTIC ANTIBODIES

用催化抗体治疗代谢疾病

• 批准号: 2144444
• 负责人: DONALD M HILVERT
• 金额: $ 19.52万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2144444
• 关键词: abzyme; active sites; enzyme therapy; gene therapy; haptens; immunotherapy; inborn aminoacid metabolism disorder; inborn lipid /lipoprotein disorder; laboratory mouse; lipoprotein lipase; nonhuman therapy evaluation; ornithine carbamoyltransferase

DESCRIPTION (Investigator's Abstract): It has recently become possible to exploit the diversity of the humeral immune system to create antibodies with tailored catalytic activities and specificities (i.e., abzymes). Because the properties of these catalysts are defined by the structure of the transition state analog that serves as the immunizing antigen, this technology provides a powerful and general method for preparing enzyme-like molecules on demand for practical applications in chemistry, biology and medicine. For example, the specificity and biocompatibility of immunoglobulin catalysts make them potentially attractive as agents for effecting vital chemical reactions in vivo. In order to investigate the feasibility of using abzymes to treat mammalian genetic diseases, two model systems will be investigated. Antibodies will be prepared that mimic the enzymes lipoprotein lipase and ornithine transcarbamoylase which play key roles in lipid and amino acid (arginine) metabolism, respectively. Operationally, the experimental approach to be followed has three steps. First, transition state analogs for the two acyl transfer reactions will be synthesized and used to generate antibodies. Second, the immune response to these compounds will be screened for efficient catalysts, the best of which will be characterized in chemical and structural detail. Third, the chemically most efficient abzymes will be evaluated in murine models of the two enzyme deficiencies. By targeting metabolic disorders caused by defective extra- and intracellular enzymes (lipoprotein lipase and ornithine transcarbamoylase, respectively) it will be possible to evaluate the efficacy of abzymes in both enzyme replacement and somatic gene therapies. The use of catalytic antibodies to treat mammalian diseases promises to be especially important in those cases where natural enzymes are unavailable, difficult to engineer, unstable, or otherwise unsuitable for therapeutic application. If successful, the proposed experiments will not only provide novel pharmacologically active proteins but also valuable tools for probing cellular metabolism and for dissecting the fundamental mechanisms by which proteins catalyze chemical reactions.

描述（调查员的摘要）：最近有可能 利用肱骨免疫系统的多样性来产生抗体 具有量身定制的催化活性和特异性（即abzymes）。 因为这些催化剂的特性是由结构定义的 作为免疫抗原的过渡状态类似物， 技术提供了一种强大而通用的方法来制备类似酶的方法 分子按需在化学，生物学和 药品。 例如， 免疫球蛋白催化剂使其作为代理具有吸引力 在体内影响重要的化学反应。 为了调查 使用abzymes治疗哺乳动物遗传疾病的可行性，两个模型 系统将进行研究。 抗体将准备好模仿 酶脂蛋白脂肪酶和鸟氨酸经carbamoylase，播放钥匙 分别在脂质和氨基酸（精氨酸）代谢中作用。 在操作上，要遵循的实验方法有三个步骤。 首先，两个酰基转移反应的过渡状态类似物将是 合成并用于生成抗体。 其次，免疫反应 将这些化合物筛选为有效的催化剂，最好的催化剂 这将以化学和结构细节为特征。 第三， 化学上最有效的abzymes将在鼠模型中评估 两种酶缺陷。 通过针对由 细胞外酶有缺陷（脂蛋白脂肪酶和 分别可以评估鸟氨酸经carbamoylase） abzymes在酶替代和体细胞基因中的功效 疗法。 使用催化抗体治疗哺乳动物疾病 在天然酶的情况下，承诺尤其重要 不可用，难以设计，不稳定或其他不合适 用于治疗应用。如果成功，建议的实验将 不仅提供新颖的药理学活性蛋白，而且还提供有价值的蛋白质 探测细胞代谢和剖析基本的工具 蛋白质催化化学反应的机制。