THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES AND OTHER BIOLOGICAL LIGANDS

在单抗(或其他生物配体)可以标记或 杀死一个肿瘤细胞，它通常必须到达那个细胞。对于部分 肿瘤距离最近的血管超过几微米，可接近 受限于分子可以通过 细胞外空间。我们正在研究空间和时间 免疫球蛋白(Ig)扩散和扩散分布的分布 通过肿瘤的对流，考虑到特定的结合， 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。重大预测：(1)抗体 分子可以被阻止穿透肿瘤的事实本身 它们成功地与抗原结合(“结合部位屏障”)。因此， 有时，亲和力较低可能更可取。(2)即使是可饱和的 结合(但不是新陈代谢)，肿瘤细胞暴露于 抗体在整个肿块中都是一样的。(3)新陈代谢会 减少细胞的相对“C×T”暴露距离较远 血管。这可能是有效治疗的一个主要障碍。 带有配体分子的实体瘤。 该模型的预测已经用皮下肿瘤和 豚鼠的微转移。我们使用了双重标记的组合 放射自显影和双生色团免疫组织化学检测 同时，抗体的微观分布，同型匹配 控制免疫球蛋白、抗原和血管。在这两个S.C.肿瘤中的结果 而微转移则直接通过实验验证了我们的 “场地屏障”假说。 我们推测，“结合部位障碍”是导致 生理性自分泌/旁分泌和内分泌分子的进化。 因此，我们认为应该把微药理学纳入其中 考虑到我们为外源设计下一代这样的分子 给药或转基因细胞分泌。

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.