Gillies S D, Lan Y, Wesolowski J S, Qian X, Reisfeld R A, Holden S, Super M, Lo K M
Lexigen Pharmaceuticals Corp., Lexington, MA 02137, USA.
J Immunol. 1998 Jun 15;160(12):6195-203.
IL-12 is a complex cytokine in both its structure and its range of biologic activities. Fusions of this heterodimeric molecule with an intact antitumor Ab were made to test the feasibility and efficacy of targeting IL-12 to tumors to elicit a local immune response. Fusion proteins composed of the human p35 and p40 subunits had IL-12 bioactivities that were nearly as potent on human immune cells as the rIL-12 standard, but were inactive on mouse cells. Hybrid IL-12 fusion proteins composed of mouse p35 and human p40, fused to Ab, were capable of inducing IFN-gamma, but were much less active on mouse spleen cells than a mouse IL-12 standard. Despite this relatively low activity, the hybrid fusion protein was as effective in a SCID mouse model as a fully active Ab-IL-2 fusion protein in eliminating established pulmonary metastases of CT26 colon carcinoma. Specific targeting of a human IL-12 fusion protein to metastatic prostate carcinoma xenografts was also shown to be effective in SCID mice transplanted with human lymphocyte-activated killer cells. These results demonstrate the importance of directing this potent cytokine to the tumor microenvironment and suggest an important alternative to systemic IL-12 administration or gene therapy for increasing its therapeutic index.
白细胞介素-12在其结构和生物活性范围方面都是一种复杂的细胞因子。将这种异二聚体分子与完整的抗肿瘤抗体进行融合，以测试将白细胞介素-12靶向肿瘤以引发局部免疫反应的可行性和有效性。由人p35和p40亚基组成的融合蛋白具有白细胞介素-12生物活性，其对人免疫细胞的作用几乎与重组白细胞介素-12标准品一样有效，但对小鼠细胞无活性。由小鼠p35和人p40组成并与抗体融合的杂交白细胞介素-12融合蛋白能够诱导γ干扰素，但对小鼠脾细胞的活性远低于小鼠白细胞介素-12标准品。尽管活性相对较低，但在SCID小鼠模型中，这种杂交融合蛋白在消除已建立的CT26结肠癌肺转移方面与完全活性的抗体-白细胞介素-2融合蛋白一样有效。在移植了人淋巴细胞激活杀伤细胞的SCID小鼠中，人白细胞介素-12融合蛋白对转移性前列腺癌异种移植物的特异性靶向也被证明是有效的。这些结果证明了将这种强效细胞因子导向肿瘤微环境的重要性，并提示了一种重要的替代方法，可替代全身给予白细胞介素-12或基因治疗以提高其治疗指数。
