Pretargeted Antibodies with Infinite Affinity

描述(由申请人提供)：这项研究项目的长期目标是能够生产出用于癌症预靶向诊断和治疗的创新分子集。本提案涉及一项合作努力，寻求使用工程抗体靶向的放射治疗来最大限度地提高复发B细胞淋巴瘤的治愈率。 这一应用的重点是前靶向，它将抗体在肿瘤中的缓慢积累与辐射的传递分开。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的融合蛋白来实现这一点。在给药后，融合蛋白被定位在肿瘤中，并从循环中清除，一个连接到放射性核素的小配体可以被预先针对肿瘤的配体结合蛋白迅速捕获。 利用基本的化学原理，我们的实验室开发出了抗体/配体对，它们保留了抗体的结合特异性，但不会解离。通过消除配体与抗体的解离，产生不可逆抗体(IAb)，我们使亲和力功能无限。与目前用于预靶向应用的链霉亲和素-生物素系统相比，人性化格式的不可逆结合提供了显着的改进。 这里提出的工作是一项用于体内放射治疗预靶向传递的不可逆抗体的合作研究。我们的实验室将设计、制备和表征同时具有抗肿瘤和不可逆抗配体结合活性的新型工程蛋白。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用于肿瘤预靶向的新IAb结构的特性，并与使用放射性标记抗肿瘤抗体的传统放射免疫疗法和链霉亲和素-生物素预靶向方法进行比较。

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.