Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR.
Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR.
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用于表达 de2-7 EGFR 或扩增 EGFR 的肿瘤靶向免疫治疗的嵌合单克隆抗体 806 (ch806) 的工程和表征。
DOI：
10.1038/sj.bjc.6602470
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发表时间：
2005-03-28
影响因子：
8.8
通讯作者：
Scott, AM
中科院分区：
文献类型：
--
作者：
Panousis, C;Rayzman, VM;Johns, TG;Renner, C;Liu, Z;Cartwright, G;Lee, FT;Wang, D;Gan, H;Cao, D;Kypridis, A;Smyth, FE;Brechbiel, MW;Burgess, AW;Old, LJ;Scott, AM
我们报道了一种嵌合单克隆抗体（ch806）的产生，该抗体对表皮生长因子受体（EGFR）上的表位具有特异性，与所有其他抗EGFR疗法的靶向抗体不同。Ch806抗体对de2-7和过表达的野生型（wt） EGFR都有反应，但对正常组织中生理水平上表达的天然EGFR没有反应。Ch806在CHO （DHFR−/−）细胞中稳定表达，纯化用于后续表征，并验证用于初步免疫治疗研究。Ch806保留了小鼠亲本抗体的抗原结合特异性和亲和力。此外，在人效应细胞存在的情况下，ch806对表达806抗原的靶细胞表现出增强的抗体依赖性细胞毒性。Ch806被成功地用碘-125和铟-111进行放射性标记，而没有失去抗原结合亲和力或特异性。放射免疫偶联物在37℃的人血清中稳定存在长达9天，在裸鼠体内显示出约78小时的终末半衰期（T1/2β）。在携带de2-7 egfr表达或扩增egfr表达异种移植物的BALB/c裸鼠中进行的生物分布研究显示，125i标记的ch806没有显示任何显著的肿瘤保留。然而，在注射后7天，' 111in标记的ch806被证明具有特异性和长期的肿瘤定位，摄取了31%的id g - 1，并且观察到肿瘤与血液的比例为5:1。体内治疗研究表明，与对照组相比，ch806对BALB/c裸鼠的de2-7 EGFR异种移植物有显著的抗肿瘤作用，小鼠806和抗EGFR 528抗体都有明显的抗肿瘤作用。这些结果支持ch806在治疗合适的egfr表达肿瘤中的潜在治疗作用，并值得进一步研究ch806作为治疗剂的潜力。
We report the generation of a chimeric monoclonal antibody (ch806) with specificity for an epitope on the epidermal growth factor receptor (EGFR) that is different from that targeted by all other anti-EGFR therapies. Ch806 antibody is reactive to both de2-7 and overexpressed wild-type (wt) EGFR but not native EGFR expressed in normal tissues at physiological levels. Ch806 was stably expressed in CHO (DHFR −/−) cells and purified for subsequent characterisation and validated for use in preliminary immunotherapy investigations. Ch806 retained the antigen binding specificity and affinity of the murine parental antibody. Furthermore, ch806 displayed enhanced antibody-dependent cellular cytotoxicity against target cells expressing the 806 antigen in the presence of human effector cells. Ch806 was successfully radiolabelled with both iodine-125 and indium-111 without loss of antigen binding affinity or specificity. The radioimmunoconjugates were stable in the presence of human serum at 37°C for up to 9 days and displayed a terminal half-life (T1/2β) of approximately 78 h in nude mice. Biodistribution studies undertaken in BALB/c nude mice bearing de2-7 EGFR-expressing or amplified EGFR-expressing xenografts revealed that 125I-labelled ch806 failed to display any significant tumour retention. However, specific and prolonged tumour localisation of' 111In-labelled ch806 was demonstrated with uptake of 31%ID g−1 and a tumour to blood ratio of 5 : 1 observed at 7 days postinjection. In vivo therapy studies with ch806 demonstrated significant antitumour effects on established de2-7 EGFR xenografts in BALB/c nude mice compared to control, and both murine 806 and the anti-EGFR 528 antibodies. These results support a potential therapeutic role of ch806 in the treatment of suitable EGFR-expressing tumours, and warrants further investigation of the potential of ch806 as a therapeutic agent.
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影响因子：
10.3
作者：
Busam, KJ;Capodieci, P;Halpern, AC
通讯作者：
Halpern, AC
影响因子：
2.9
作者：
CHOMCZYNSKI, P;SACCHI, N
通讯作者：
SACCHI, N
影响因子：
56.9
作者：
FRY, DW;KRAKER, AJ;BRIDGES, AJ
通讯作者：
BRIDGES, AJ
影响因子：
6.4
作者：
HILLS, D;ROWLINSONBUSZA, G;GULLICK, WJ
通讯作者：
GULLICK, WJ
影响因子：
64.8
作者：
HUNTER, WM;GREENWOOD, FC
通讯作者：
GREENWOOD, FC