Van Ostade X, Vandenabeele P, Everaerdt B, Loetscher H, Gentz R, Brockhaus M, Lesslauer W, Tavernier J, Brouckaert P, Fiers W
Laboratory of Molecular Biology, University of Gent, Belgium.
Nature. 1993 Jan 21;361(6409):266-9. doi: 10.1038/361266a0.
The remarkable ability of tumour necrosis factor (TNF), especially in combination with interferon, selectively to kill or inhibit malignant cell lines is so far unmatched by any other combination of cytokines. But clinical trials in cancer patients have on the whole been disappointing, and it has been estimated that a TNF dose would be effective only at 5-25 times the maximum tolerated dose. High TNF concentrations give a much more pronounced antitumour activity in mice, in which murine TNF is about 50-fold more systemically toxic than human TNF. But there is little or no species specificity in cytotoxicity of murine TNF and human TNF on human as well as on murine cell lines. This dual action of TNF may be explained by the existence of two types of receptor for TNF: the smaller, TNF-R55, is present on most cells and particularly on those susceptible to the cytotoxic action of TNF; the larger, TNF-R75, is also present on many cell types, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes. In mice, human TNF binds only to murine TNF-R55 (ref. 15), which can then mediate cytotoxic activity on malignant cells. As human TNF does not bind to murine TNF-R75, the latter must be responsible for the much enhanced systemic toxicity of murine TNF. Human TNF can, however, become toxic in mice when a second pathway is activated. There is no reciprocal situation in the human system: human and murine TNF bind almost equally well to the two human TNF receptors. Here we describe human TNF mutants that sill interact with the human TNF-R55 receptor but which have largely lost their ability to bind to human TNF-R75. Activation of TNF-R55 is sufficient to trigger cytotoxic activity towards transformed cells. One representative human TNF mutant retains its antitumour activity in nude mice carrying tumours derived from human cancers. Under the appropriate conditions, such human TNF mutants are expected to induce less systemic toxicity in man, while still exerting their direct antitumour effect.
肿瘤坏死因子（TNF）具有非凡的能力，尤其是与干扰素联合使用时，能选择性地杀死或抑制恶性细胞系，这是目前其他任何细胞因子组合都无法比拟的。但总体而言，针对癌症患者的临床试验结果令人失望，据估计，TNF剂量只有在最大耐受剂量的5至25倍时才会有效。高浓度的TNF在小鼠体内具有更显著的抗肿瘤活性，其中鼠源TNF的全身毒性比人源TNF高约50倍。但鼠源TNF和人源TNF对人及鼠细胞系的细胞毒性几乎没有物种特异性。TNF的这种双重作用可能是由于存在两种TNF受体：较小的TNF-R55存在于大多数细胞上，特别是那些易受TNF细胞毒性作用影响的细胞；较大的TNF-R75也存在于许多细胞类型中，尤其是髓系来源的细胞，并且在受刺激的T和B淋巴细胞上强烈表达。在小鼠中，人源TNF仅与鼠源TNF-R55结合（参考文献15），然后可介导对恶性细胞的细胞毒性活性。由于人源TNF不与鼠源TNF-R75结合，后者必定是鼠源TNF全身毒性大幅增强的原因。然而，当第二条途径被激活时，人源TNF在小鼠体内也会产生毒性。在人体系统中不存在相反的情况：人源和鼠源TNF与两种人源TNF受体的结合能力几乎相同。在此，我们描述了一些人源TNF突变体，它们仍能与人源TNF-R55受体相互作用，但与人类TNF-R75结合的能力已基本丧失。TNF-R55的激活足以引发对转化细胞的细胞毒性活性。一种代表性的人源TNF突变体在携带源自人类癌症肿瘤的裸鼠中保留了其抗肿瘤活性。在适当条件下，预计此类人源TNF突变体在人体内引起的全身毒性较小，同时仍能发挥其直接抗肿瘤作用。
