Antibody/chelate conjugates

该项目的具体目标是与项目1和项目2相互作用，开发用于临床的改进的双功能螯合剂技术。在下一个资助期，我们的计划是继续多肽库的生产和筛选工作。我们最初的九个残基，四个位置的文库被配置为遵守预标记的限制，因此缺少带有带电侧链的氨基酸残基。它已经产生了几个有趣的生物测试候选者。然而，目前可用的90Y的质量如此之高，以至于预贴标签的要求比以前更低。DOTA多肽免疫结合物的常规后标记允许使用含有带电侧链的多肽。带电残基的加入可以产生具有相当好的底物性能以及改善的溶解性的试剂。它们将被合成，连接到抗体上，进行放射性标记，并在体外作为组织酶底物进行测试。生物分布动物研究将在从体外研究中选择的多肽的结合物上进行。在拟议的3年周期结束时，我们预计将彻底表征大约6-9个可供人类使用的多肽连接体的化学和生理特性。作为一个集合，这些结果将为我们提供一个有用的视角，了解通过这种方法可以实现的效果。所开发的一套连接子应该对药物输送领域的其他研究人员有相当大的用处。

The specific aims of this project are to interact with Projects 1 and 2 to develop improved bifunctional chelating agent technology for clinical use. For the next grant period, our plans are to Continue work on peptide library production and screening. Our initial nine-residue, four-position library was configured to obey the constraints of pre-labeling, and thus lacks amino acids residues with charged side chains. It has produced several interesting candidates for biological testing. However, the presently available 90Y is of such quality that pre-labeling is less of a requirement than previously. Conventional post-labeling of DOTA peptide immunoconjugates allows use of peptides containing charged side chains. The inclusion of charged residues could lead to reagents with considerably better substrate properties as well as improved solubility. These will be synthesized, conjugated to antibodies, radiolabeled and tested as cathepsin substrates in vitro. Biodistribution animal studies will be carried out on conjugates of the peptides selected from in vitro studies. At the end of the proposed 3 year period, we expect to have thoroughly characterized the chemical and physiological properties of approximately 6-9 peptide linkers as candidates for human use. Taken as a set, these results will give us a useful perspective on the effects that can be achieved by this approach. The set of linkers developed should be of considerable use to other researchers in the area of drug delivery.