High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules.
High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules.
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发表时间：
2001-06
期刊：
影响因子：
11.2
通讯作者：
G. Adams;R. Schier;A. McCall;H. Simmons;E. Horak;R. Alpaugh;J. Marks;L. Weiner
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文献类型：
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作者：
G. Adams;R. Schier;A. McCall;H. Simmons;E. Horak;R. Alpaugh;J. Marks;L. Weiner
抗肿瘤单克隆抗体必须以高亲和力结合肿瘤抗原以实现持久的肿瘤保留。这刺激了产生用于癌症治疗的高亲和力抗体的努力。然而，已经假设抗体和肿瘤抗原之间非常高的亲和力相互作用可能损害单克隆抗体的有效肿瘤穿透，从而降低有效的体内靶向（K. Fujimori等人，J. Nucl. Med.，31：1191-1198，1990）。在这里，我们表明，内在的亲和特性调节抗肿瘤单链抗体（scFv）分子的定量递送到实体瘤和scFv从血管系统渗透到肿瘤块。在生物分布研究中，检查了一系列亲和力范围为10（-7）-10（-11）M的放射性碘标记的scFv突变体，定量肿瘤保留没有随着亲和力超过10（-9）M的增强而显著增加。当在无肾小鼠中不存在肾清除的情况下评价scFv时，观察到类似的分布模式，表明scFv的快速肾清除不是这些观察结果的原因。静脉内施用scFv亲和力突变体后肿瘤切片的IHC和IF评价显示，最低亲和力分子表现出弥漫性肿瘤染色，而最高亲和力scFv主要保留在肿瘤的血管周围区域中。这些结果表明，具有极高亲和力的基于抗体的分子具有受损的肿瘤穿透特性，这在基于抗体的癌症疗法的设计中必须考虑。
Antitumor monoclonal antibodies must bind to tumor antigens with high affinity to achieve durable tumor retention. This has spurred efforts to generate high affinity antibodies for use in cancer therapy. However, it has been hypothesized that very high affinity interactions between antibodies and tumor antigens may impair efficient tumor penetration of the monoclonal antibodies and thus diminish effective in vivo targeting (K. Fujimori et al., J. Nucl. Med., 31: 1191-1198, 1990). Here we show that intrinsic affinity properties regulate the quantitative delivery of antitumor single-chain Fv (scFv) molecules to solid tumors and the penetration of scFv from the vasculature into tumor masses. In biodistribution studies examining a series of radioiodinated scFv mutants with affinities ranging from 10(-7)-10(-11) M, quantitative tumor retention did not significantly increase with enhancements in affinity beyond 10(-9) M. Similar distribution patterns were observed when the scFv were evaluated in the absence of renal clearance in anephric mice, indicating that the rapid renal clearance of the scFv was not responsible for these observations. IHC and IF evaluations of tumor sections after the i.v. administration of scFv affinity mutants revealed that the lowest affinity molecule exhibited diffuse tumor staining whereas the highest affinity scFv was primarily retained in the perivascular regions of the tumor. These results indicate that antibody-based molecules with extremely high affinity have impaired tumor penetration properties that must be considered in the design of antibody-based cancer therapies.