THE PERCOLATION OF MONOCLONAL ANTIBODIES INTO TUMORS

在单抗(或其他生物配体)可以标记之前 或者杀死一个肿瘤细胞，它必须首先到达那个细胞。对于部分 肿瘤远离最近的血管或其他来源的肿瘤 抗体，访问可能受到分子速度的限制 可以“渗入”细胞外空间。我们是 免疫球蛋白的时空分布研究 (IG)通过扩散和对流产生的分布 肿瘤，考虑到(A)饱和的可能性 与细胞的特异性结合，(B)不可饱和的、非特异性的结合， 和(C)代谢退化。 我们首先建立了渗流过程的理论模型。 到目前为止，重要的预测包括：(1) 扩散系数和/或水力传导性可能会限制通量 抗肿瘤免疫球蛋白通过肿瘤。(2)非约束性流量 控制Ig不太可能受到扩散或 对流。非特异性免疫球蛋白的穿透力越来越强 快速进入肿瘤。(3)即使是可饱和装订(但不是 新陈代谢)，即肿瘤细胞对抗体的“C乘T”暴露。 在整个质量中都是一样的。(4)新陈代谢减少 离源头较远的细胞的相对“C×T”曝光量。 这可能是实体瘤有效治疗的主要障碍。 配基分子。(5)最有趣的是，抗体水平低 在一定剂量下，亲和力可能比高亲和力更可取 用于某些治疗应用的亲和力。 我们计划使用微转移来测试模型的预测。 裸鼠体内的人黑色素瘤。抗体的分布将是 由荧光技术和放射自显影技术确定。 从这项研究中产生的概念被应用到设计中 用单抗进行的临床研究。 除了研究免疫球蛋白和其他 配体作为给药药物，我们正在考虑生理学 内源性分子物种，包括淋巴因子和 增长因素。

Before a monoclonal antibody (or other biological ligand) can label or kill a tumor cell, it must first reach that cell. For portions of a tumor far from the nearest blood vessel or other source of antibody, 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 the possibilities of (a) saturable specific binding to cells, (b) nonsaturable, nonspecific binding, and (c) metabolic degradation. We first developed theoretical models of the percolation process. Significant predictions thus far include the following: (1) The diffusion coefficient and/or hydraulic conductivity may limit flux of antitumor Ig through tumors. (2) The flux of non-binding control Ig is much less likely to be limited by diffusion or convection. Nonspecific Ig's penetrate more deeply and more quickly into the tumor. (3) Even with saturable binding (but not metabolism), the "C times T" exposure of tumor cells to antibody will be the same throughout the mass. (4) Metabolism will decrease the relative "C times T" exposure of cells farther from the source. This may be a major barrier to effective treatment of solid tumors with ligand molecules. (5) Most interesting, antibodies with low affinity may be preferable at a given dose to those with high affinity for some therapeutic applications. We plan to test predictions of the model using micrometastases of human melanoma in nude mice. The distribution of antibody will be determined by fluorescence techniques and autoradiography. Concepts arising from this study are being applied to the design of clinical studies with monoclonal antibodies. In addition to the investigations of immunoglobulin and other ligands as administered agents, we are considering the physiology of endogenous molecular species including the lymphokines and growth factors.