THE PERCOLATION OF MONOCLONAL ANTIBODIES INTO TUMORS

在单克隆抗体（或其他生物配体）可以标记 或杀死肿瘤细胞，它必须首先到达该细胞。 部分的 肿瘤远离最近的血管或其他来源， 抗体，访问可能会受到限制的速度，分子 可以通过细胞外间隙"渗透"。 我们 研究免疫球蛋白的时空分布 (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）不饱和的非特异性结合， 和（c）代谢降解。 我们首先建立了渗流过程的理论模型。 迄今为止，重要的预测包括：（1） 扩散系数和/或水力传导率可限制通量 抗肿瘤IG免疫球蛋白通过肿瘤。 (2)非约束性的通量 对照IG不太可能受到扩散或 对流 非特异性IG的渗透更深， 迅速进入肿瘤。 (3)即使有饱和结合（但不 代谢），肿瘤细胞对抗体的"C × T"暴露 在整个质量中都是一样的。 (4)新陈代谢会减少 距离辐射源较远的细胞的相对"C × T"暴露。 这可能是有效治疗实体瘤的主要障碍 配体分子。 (5)最有趣的是，抗体与低 在给定剂量下，对于具有高亲和力的那些， 对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， 裸鼠中的人黑素瘤。 抗体的分布将是 通过荧光技术和放射自显影测定。 从这项研究中产生的概念正在应用到设计中 单克隆抗体的临床研究。 除了免疫球蛋白和其他的研究之外， 配体作为管理剂，我们正在考虑的生理 包括淋巴因子在内的内源性分子种类， 生长因子

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.