Di Matteo Paola, Curnis Flavio, Longhi Renato, Colombo Giorgio, Sacchi Angelina, Crippa Luca, Protti Maria Pia, Ponzoni Mirco, Toma Salvatore, Corti Angelo
Department of Biological and Technological Research, San Raffaele H Scientific Institute, 20132 Milan, Italy.
Mol Immunol. 2006 Apr;43(10):1509-18. doi: 10.1016/j.molimm.2005.10.009. Epub 2005 Dec 7.
Tumor homing peptides containing the NGR motif, such as CNGRC and GNGRG, have been used for delivering cytokines, chemotherapeutic drugs, apoptotic peptides, and liposomes to a CD13 isoform expressed in tumor blood vessels. In view of the potential clinical applications of these drugs and considering the risk that NGR peptides could elicit blocking antibodies we have investigated the immunogenic properties of CNGRC and GNGRG in mice and rabbits, using various products containing these residues and different administration schedules. The results suggest that the immunogenicity of the NGR motif is very low, even when it is conjugated to tumor necrosis factor-alpha or to highly immunogenic carrier proteins. Molecular dynamics simulation experiments showed that both peptides have a strong propensity to populate a turn conformation. Superposition of predicted structures to the CTGNGRGEWKC loop of the 5th type I repeat of human fibronectin, a protein that contains four NGR motives, showed that the root mean square deviation of backbones was 0.7A for GNGRG and 0.5A for NGR. These results suggest that NGR peptides could mimic from an immunological point of view a "self" structure, likely the GNGRG loop of fibronectin, with important implications for the use of these targeting peptides in patients.
含有NGR基序的肿瘤归巢肽，如CNGRC和GNGRG，已被用于将细胞因子、化疗药物、凋亡肽和脂质体递送至肿瘤血管中表达的CD13同种型。鉴于这些药物的潜在临床应用，并考虑到NGR肽可能引发阻断抗体的风险，我们使用含有这些残基的各种产品和不同的给药方案，研究了CNGRC和GNGRG在小鼠和兔子中的免疫原性。结果表明，即使NGR基序与肿瘤坏死因子-α或高免疫原性载体蛋白偶联，其免疫原性也非常低。分子动力学模拟实验表明，这两种肽都有强烈的倾向形成转角构象。将预测结构与人纤连蛋白第5个I型重复序列的CTGNGRGEWKC环（一种含有四个NGR基序的蛋白质）叠加，结果显示，GNGRG的主链均方根偏差为0.7埃，NGR为0.5埃。这些结果表明，从免疫学角度来看，NGR肽可能模拟一种“自身”结构，可能是人纤连蛋白的GNGRG环，这对这些靶向肽在患者中的应用具有重要意义。
