THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES AND OTHER BIOLOGICAL LIGANDS

单克隆抗体和其他生物配体的药理学

• 批准号: 3796466
• 负责人: J N WEINSTEIN
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3796466
• 关键词: antigen antibody reaction; autoradiography; biological transport; blood vessels; chemical binding; diffusion; extracellular; guinea pigs; immunocytochemistry; immunoglobulin G; immunopharmacology; ligands; mathematical model; metastasis; model design /development; monoclonal antibody; neoplasm /cancer immunotherapy; neoplastic cell; radionuclide double label

Before a monoclonal antibody (or other biological ligand) can label or kill a tumor cell, it must generally reach that cell. For portions of a tumor more than a few microns from the nearest blood vessel, access may be limited by the rate at which the molecule can "percolate" through the extracellular space. We are investigating the spatial and temporal profiles of immunoglobulin (Ig) distribution generated by diffusion and convection through tumors, taking into account specific binding, nonspecific binding, and metabolism. For this purpose, we developed theoretical models that splice together the global pharmacology and the microscopic percolation process. Significant predictions: (1) Antibody molecules may be prevented from penetrating a tumor by the very fact of their successful binding to antigen (the "binding site barrier"). Thus, lower affinity might sometimes be preferable. (2) Even with saturable binding (but not metabolism), the "C times T" exposure of tumor cells to antibody will be the same throughout the mass. (3) Metabolism will decrease the relative "C times T" exposure of cells farther from the blood vessel. This may be a major barrier to effective treatment of solid tumors with ligand molecules. Predictions of the model have been tested using subcutaneous tumors and micrometastases in guinea pigs. We used a combination of double-label autoradiography and double-chromophore immunohistochemistry to determine simultaneously the microscopic distribution of antibody, isotype matched control IgG, antigen, and blood vessels. The result in both S.C. tumors and micrometastases was direct experimental validation of our "binding site barrier" hypothesis. We have speculated that the "binding site barrier" is a factor in the evolution of physiological autocrine/paracrine and endocrine molecules. As a corollary, we think that the micropharmacology should be taken into account as we design the next generation of such molecules for exogenous administration or for secretion by genetically modified cells.

在单克隆抗体（或其他生物配体）可以标记或 杀死肿瘤细胞，它通常必须到达细胞。 的部份的 肿瘤距离最近的血管超过几微米， 受到分子可以“渗透”通过膜的速率的限制。 细胞外间隙 我们正在调查 扩散和产生的免疫球蛋白（IG）分布概况 通过肿瘤的对流，考虑到特异性结合， 非特异性结合和代谢。 为此，我们开发了 将全球药理学和 微观渗流过程 重要预测：（1）抗体 分子可能会被阻止穿透肿瘤，因为事实上 它们与抗原的成功结合（“结合位点屏障”）。 因此，在本发明中， 较低的亲和力有时可能是优选的。(2)即使是饱和的 结合（但不是代谢），肿瘤细胞的“C × T”暴露于 抗体在整个质量中是相同的。(3)新陈代谢会 降低远离细胞的相对“C乘T”暴露， 血管 这可能是有效治疗的主要障碍。 有配体分子的实体瘤。 该模型的预测已经使用皮下肿瘤进行了测试， 豚鼠的微转移。 我们使用了双重标签的组合 放射自显影和双发色团免疫组织化学来确定 同时，抗体的微观分布，同种型匹配 对照IgG、抗原和血管。 结果在两个S.C.肿瘤 和微转移是我们的“结合”的直接实验验证 “位垒”假说。 我们推测，“结合位点屏障”是一个因素， 生理自分泌/旁分泌和内分泌分子的进化。 作为一个推论，我们认为，微药理学应考虑到 考虑到我们设计下一代这样的分子， 施用或用于通过遗传修饰的细胞分泌。