Pretargeted Antibodies with Infinite Affinity

描述（由申请人提供）：该研究项目的长期目标是能够生产用于癌症的预先靶向诊断和治疗的创新分子组。目前的建议涉及一个合作的努力，寻求最大限度地提高复发性B细胞淋巴瘤的治愈率，使用由工程抗体靶向放射治疗。 该应用的重点是预靶向，其将抗体在肿瘤中的缓慢积累与辐射的递送分开。我们将通过设计和表达由抗肿瘤抗体和配体结合蛋白的基因制备的新融合蛋白来实现这一点。在融合蛋白被施用、定位在肿瘤中并从循环中清除后，与放射性核素连接的小配体可以被预先靶向肿瘤的配体结合蛋白快速捕获。 使用基本的化学原理，我们的实验室已经开发出抗体/配体对，保留抗体的结合特异性，但不解离。通过消除配体与抗体的解离，以产生不可逆抗体（iAb），我们已经使亲和力在功能上无限大。人源化形式的不可逆结合提供了对目前用于预靶向应用的链霉亲和素-生物素系统的显著改进。 这里提出的工作是一个合作调查的不可逆抗体的预靶向输送放射治疗在体内。我们的实验室将设计，制备和表征新的工程蛋白质，结合抗肿瘤和不可逆的抗配体结合活性。我们在Press博士实验室的合作者将使用小鼠模型系统来研究这些新的iAb构建体用于肿瘤预靶向的特性，与使用放射性标记的抗肿瘤抗体和链霉亲和素-生物素预靶向方法的传统放射免疫疗法进行比较。

DESCRIPTION (provided by applicant): The long-range goal of this research project is to enable the production of innovative sets of molecules for the pretargeted diagnosis and therapy of cancer. The present proposal involves a collaborative effort that seeks to maximize the cure rate of relapsed B cell lymphomas using radiotherapy targeted by engineered antibodies. The focus of this application is pretargeting, which separates the slow accumulation of an antibody in a tumor from the delivery of radiation. We will do this by designing and expressing new fusion proteins prepared from the genes of an antitumor antibody and a ligand-binding protein. After the fusion protein has been administered, localized in the tumor and cleared from the circulation, a small ligand linked to a radionuclide can be captured quickly by the ligand-binding protein pretargeted at the tumor. Using fundamental chemical principles, our lab has developed antibody/ligand pairs that retain the binding specificity of the antibody, but do not dissociate. By eliminating the dissociation of the ligand from the antibody, to produce an irreversible antibody (iAb), we have made the affinity functionally infinite. Irreversible binding in a humanizable format offers striking improvements over the streptavidin-biotin system currently used for pretargeting applications. The work proposed here is a collaborative investigation of irreversible antibodies for the pretargeted delivery of radiotherapy in vivo. Our lab will design, prepare, and characterize new engineered proteins incorporating both antitumor and irreversible anti-ligand binding activity. Our collaborators in Dr. Press' laboratories will use a mouse model system to study the properties of these new iAb constructs for tumor pretargeting, in comparison with conventional radioimmunotherapy using radiolabeled antitumor antibodies and with streptavidin-biotin pretargeting approaches.