Academic Department of Clinical Oncology, City Hospital Campus, University of Nottingham, Nottingham, UK.
PLoS One. 2013;8(2):e54892. doi: 10.1371/journal.pone.0054892. Epub 2013 Feb 8.
Several monoclonal antibodies (mAbs) recognising Lewis(y), such as BR96, have reached the clinic but have failed to show good anti-tumour responses with an acceptable level of toxicity. No Lewis(b) mAbs have been trialled in patients. In this study we compare the specificity of three mAbs; BR96 (Lewis(y)), 2-25 LE (Lewis(b)) and 692/29 that recognises a unique facet of both Lewis(y) and Lewis(b). We then assessed the in vivo therapeutic effect of 692/29 using xenograft models.
METHODOLOGY/PRINCIPAL FINDINGS: Using a glycan array, each mAb was shown to display a different binding pattern with only 692/29 binding to both Lewis(y) and Lewis(b). 692/29 was able to kill tumour cells over-expressing Lewis(y/b) directly, as well as by antibody and complement mediated cytotoxicity (ADCC/CDC), but failed to kill cells expressing low levels of these haptens. In contrast, BR96, directly killed cells expressing either high or low levels of Lewis(y) perhaps explaining its toxicity in patients. 2-25 LE failed to cause any direct killing but did mediate ADCC/CDC. Both 692/29 and BR96 bound to >80% of a panel of over 400 colorectal tumours whereas 2-25 LE showed lower reactivity (52%). 692/29 demonstrated more restricted normal tissue reactivity than both BR96 and 2-25 LE. 692/29 anti-Lewis(y/b) mAb also showed good in vivo killing in xenograft models.
CONCLUSIONS/SIGNIFICANCE: MAbs targeting both Lewis(y) and Lewis(b) may have a therapeutic advantage over mAbs targeting just one hapten. 692/29 has a more restricted normal tissue distribution and a higher antigen threshold for killing which should reduce its toxicity compared to a Lewis(y) specific mAb. 692/29 has an ability to directly kill tumours whereas the anti-Lewis(b) mAb does not. This suggests that Lewis(y) but not Lewis(b) are functional glycans. 692/29 showed good anti-tumour responses in vivo and is a strong therapeutic candidate.
几种识别 Lewis(y)的单克隆抗体（mAbs），如 BR96，已经进入临床阶段，但毒性可接受的情况下并未显示出良好的抗肿瘤反应。没有 Lewis(b)mAbs 在患者中进行过试验。在这项研究中，我们比较了三种 mAbs 的特异性；BR96（Lewis(y)）、2-25LE（Lewis(b)）和识别 Lewis(y)和 Lewis(b)独特方面的 692/29。然后，我们使用异种移植模型评估了 692/29 的体内治疗效果。
方法/主要发现：使用糖基阵列，每种 mAb 都显示出不同的结合模式，只有 692/29 与 Lewis(y)和 Lewis(b)结合。692/29 能够直接杀死过表达 Lewis(y/b)的肿瘤细胞，以及通过抗体和补体介导的细胞毒性（ADCC/CDC），但不能杀死表达这些半抗原低水平的细胞。相比之下，BR96 直接杀死表达高或低水平 Lewis(y)的细胞，这也许可以解释其在患者中的毒性。2-25LE 不能直接引起任何杀伤，但能介导 ADCC/CDC。692/29 和 BR96 均与超过 400 个结直肠癌肿瘤的面板中的 >80%结合，而 2-25LE 显示出较低的反应性（52%）。692/29 显示出比 BR96 和 2-25LE 更受限的正常组织反应性。692/29 抗 Lewis(y/b)mAb 在异种移植模型中也显示出良好的体内杀伤作用。
结论/意义：靶向 Lewis(y)和 Lewis(b)的 mAb 可能比仅靶向一个半抗原的 mAb 具有治疗优势。692/29 具有更受限的正常组织分布和更高的杀伤抗原阈值，与 Lewis(y)特异性 mAb 相比，其毒性应降低。692/29 能够直接杀死肿瘤，而抗 Lewis(b)mAb 则不能。这表明 Lewis(y)但不是 Lewis(b)是功能性聚糖。692/29 在体内显示出良好的抗肿瘤反应，是一种很有前途的治疗候选药物。
