Antibody/chelate conjugates

该项目的具体目标是与项目1和项目2相互作用，开发用于临床使用的改进的双功能螯合剂技术。在下一个资助期，我们的计划是继续研究肽库的生产和筛选。我们最初的9个残基，4个位置的文库配置服从预标记的约束，因此缺乏带电荷侧链的氨基酸残基。它已经产生了几个有趣的生物测试候选。然而，目前可用的90Y是这样的质量，预先标签的要求比以前少。传统的DOTA肽免疫偶联物的后标记允许使用含有带电侧链的肽。带电荷残基的包合可以使试剂具有更好的底物性质以及更好的溶解度。这些将被合成，结合到抗体，放射性标记和测试作为组织蛋白酶底物在体外。生物分布动物研究将对从体外研究中选择的肽偶联物进行。在提议的3年期限结束时，我们期望彻底表征大约6-9个肽连接物的化学和生理特性，作为人类使用的候选物。作为一个整体，这些结果将使我们对这种方法所能达到的效果有一个有用的看法。所开发的一套连接剂对药物输送领域的其他研究人员应该有相当大的用处。

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.