Treatment of diffuse leptomeningeal malignancy by intrathecal injection of 131I radioimmunoconjugates.

It is clear from a variety of different studies that monoclonal antibodies (MAbs), as either biological response modifiers or targeting agents, cannot be used successfully for the treatment of large tumour deposits. With whole immunoglobulin (Ig), insufficient MAb enters bulk disease to elicit a major cytotoxic effect. This is in marked contrast to the results obtained in the human xenograft/nude mouse models where relatively large tumours can be eliminated with systemically administered MAbs carrying drugs (Embelton and Garnett 1985), toxins (Thorpe et al. 1985), or radionuclides (Jones et al. 1985). Differences between the mouse model and the clinical studies include the dilution of the MAb conjugate in a relatively large circulating blood volume in patients, increased interstitial pressure in tumours as compared to normal organs (Jain 1988) and poor penetration of antibody from the systemic compartment to the interstitial space (Herlyn and Koprowski 1982). Whilst the use of antibody fragments improves their tumour penetration, this is at the expense of a faster blood clearance (Sutherland et al. 1987). The overall benefit in targeting seen with the use of antibody fragments is therefore relatively small.

从各种不同的研究中可以清楚地看到，单克隆抗体（MAb）无论是作为生物反应调节剂还是靶向制剂，都无法成功用于治疗大块肿瘤病灶。对于完整的免疫球蛋白（Ig），进入大块病灶的单克隆抗体不足，无法引发主要的细胞毒性作用。这与人类异种移植/裸鼠模型中获得的结果形成鲜明对比，在该模型中，全身给药携带药物（Embelton和Garnett，1985年）、毒素（Thorpe等人，1985年）或放射性核素（Jones等人，1985年）的单克隆抗体可以消除相对较大的肿瘤。小鼠模型和临床研究之间的差异包括：患者相对较大的循环血容量会稀释单克隆抗体偶联物，与正常器官相比肿瘤间质压力升高（Jain，1988年）以及抗体从全身循环到间质空间的渗透性差（Herlyn和Koprowski，1982年）。虽然使用抗体片段可提高其肿瘤渗透性，但这是以更快的血液清除为代价的（Sutherland等人，1987年）。因此，使用抗体片段在靶向方面的总体益处相对较小。