Belmont Heather J, Price-Schiavi Shari, Liu Bai, Card Kimberlyn F, Lee Hyung-Il, Han Kai-Ping, Wen Jinghai, Tang Shamay, Zhu Xiaoyung, Merrill Jane, Chavillaz Pierre-Andre, Wong Jeffrey L, Rhode Peter R, Wong Hing C
Altor BioScience Corporation, 2810 N Commerce Parkway, Miramar, FL 33025, USA.
Clin Immunol. 2006 Oct;121(1):29-39. doi: 10.1016/j.clim.2006.05.005. Epub 2006 Jun 30.
We previously have generated a single-chain T cell receptor-cytokine fusion protein (264scTCR/IL-2) comprising interleukin-2 genetically linked to a soluble HLA-A2.1-restricted TCR recognizing a peptide of human p53 protein. In this report, we show that 264scTCR/IL-2 inhibits the growth of primary tumors derived from the A375 (p53+/HLA-A2.1+) human melanoma and exhibits significantly better antitumor activity than recombinant human IL-2 alone. Moreover, treatment with 264scTCR/IL-2 results in tumor growth retardation in mice bearing large A375 tumors and other p53+/HLA-A2.1+ human tumors but does not affect tumor outgrowth of HLA-A2.1-negative tumors. This suggests that antigen targeting plays a substantial role in the efficacy of 264scTCR/IL-2 against p53+/HLA-A2+ tumors. Further, the antitumor activity of 264scTCR/IL-2 was found to be likely mediated by NK cell activation and tumor infiltration. A biologically active chimeric version of the molecule (c264scTCR/IL-2) also exhibits favorable pharmacokinetic properties required of a clinical candidate for this novel class of potent antitumor activities and targeted anticancer immunotherapeutics.
我们之前已经构建了一种单链T细胞受体-细胞因子融合蛋白（264scTCR/IL-2），它由与可溶性HLA-A2.1限制性TCR基因连接的白细胞介素-2组成，该TCR可识别人类p53蛋白的一个肽段。在本报告中，我们表明264scTCR/IL-2可抑制源自A375（p53+/HLA-A2.1+）人黑色素瘤的原发性肿瘤的生长，并且其抗肿瘤活性明显优于单独的重组人IL-2。此外，用264scTCR/IL-2治疗可使携带大型A375肿瘤和其他p53+/HLA-A2.1+人肿瘤的小鼠的肿瘤生长减缓，但不影响HLA-A2.1阴性肿瘤的生长。这表明抗原靶向在264scTCR/IL-2对p53+/HLA-A2+肿瘤的疗效中起重要作用。此外，发现264scTCR/IL-2的抗肿瘤活性可能是由NK细胞活化和肿瘤浸润介导的。该分子的一种生物活性嵌合形式（c264scTCR/IL-2）还表现出这类新型强效抗肿瘤活性和靶向抗癌免疫疗法的临床候选药物所需的良好药代动力学特性。
