Antibodies with Infinite Affinity

描述(申请人提供)：该项目的长期目标是开发一套创新的探针分子，用于人类癌症的靶向诊断和治疗。首选的方法是将人造受体放置在靶细胞上，然后在受体上负载一个小分子，该小分子提供用于成像或放射治疗的光子。这使得我们可以利用抗体成熟的靶点选择，与小分子的快速药代动力学相结合。我们增加了这里研究的分子以无限亲和力结合的重要特征：它们选择性地形成不解离的络合物。这允许最大限度地实现目标时间，仅受自然周转过程的限制。 传统的、高亲和力的可逆结合抗体不能有效地穿透肿瘤表面，这是肿瘤靶向治疗中的一个众所周知的问题。这通常被称为结合位点屏障，其基础是高亲和力抗体在其靶标上表现出的长结合寿命。弱结合抗体，或者更通常是它们的单价片段，不会有这个问题，因为它们经常结合和解离--但出于同样的原因，它们不会在肿瘤中停留足够长的时间来发挥作用。这种对同时具有低亲和力和高亲和力的配体的矛盾需求大大限制了抗体用于成像，尤其是用于实体肿瘤治疗的有效性。不解离的选择性结合解决了探针捕获用于肿瘤靶向的一个重要的实际问题，但也可能阻碍配体在整个肿瘤中的有效分布。另一种更微妙的选择是将弱结合与无限结合结合在一起，这应该会导致抗肿瘤抗体或工程片段对肿瘤的更有效渗透。如果我们从低亲和力的抗肿瘤抗体开始，准备可以永久结合的构建体，但只有在多次关联-解离事件之后，这应该会允许构建体不仅渗透到肿瘤中，而且最终永久地附着在它们的靶标上。

DESCRIPTION (provided by applicant): The long-term objectives of this project are to develop an innovative set of probe molecules for targeted diagnosis and therapy of human cancer. The preferred approach is to place an artificial receptor on a target cell, and then to load the receptor with a small molecule that delivers photons for imaging or radiation for therapy. This allows us to use the well-developed target selection available for antibodies, in concert with the rapid pharmacokinetics of small molecules. We add the important feature that the molecules studied here bind with infinite affinity: they selectively form complexes that do not dissociate. This allows maximum time on target, limited only by natural turnover processes. It is a well-known problem in tumor targeting that conventional, reversibly-binding antibodies with high affinity do not penetrate efficiently beyond the surface of a tumor. This is usually called the binding-site barrier, and its basis is the long bound lifetime exhibited by a high-affinity antibody on its target. Weakly binding antibodies, or more usually their monovalent fragments, do not share this problem because they bind and dissociate frequently-but for the same reason, they do not remain in the tumor long enough to be effective. This paradoxical need for ligands of simultaneous low and high affinity significantly limits the efficacy of antibodies for imaging and above all for therapy of solid tumors. Selective binding without dissociation solves an important practical problem in probe capture for tumor targeting, but may also present an obstacle to efficacious distribution of the ligand throughout the tumor. A more subtle alternative, which should lead to far more effective tumor penetration of antitumor antibodies or engineered fragments, is to combine weak with infinite binding. If we begin with low-affinity antitumor antibodies and prepare constructs that can bind permanently, but only after many association-dissociation events, this should allow the constructs not only to permeate the tumor but also to eventually attach permanently to their targets.