Hu P, Hornick J L, Glasky M S, Yun A, Milkie M N, Khawli L A, Anderson P M, Epstein A L
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Cancer Res. 1996 Nov 1;56(21):4998-5004.
A murine antihuman B-cell monoclonal antibody, Lym-1, has shown considerable promise for the treatment of human malignant lymphomas. To enhance its clinical potential, a genetically engineered fusion protein consisting of a chimeric Lym-1 (chLym-1) and interleukin 2 (IL-2) was tested for mediating cytotoxicity, increasing vasopermeability, and enhancing antibody uptake in human malignant lymphomas. The chLym-1/IL-2 fusion protein, which was expressed initially in a baculovirus system and more recently in the glutamine synthetase gene amplification system, was shown to be processed and assembled into a normal immunoglobulin monomer with two IL-2 molecules per antibody. It was found to be equivalent to the chLym-1 antibody in antigen-binding specificity and relative affinity. In addition, it maintains IL-2 cytokine activity as demonstrated by support of T-cell proliferation. Moreover, in antibody-dependent cellular cytotoxicity assays against Raji target cells, chLym-1/IL-2 had approximately 2-fold and 4-fold higher cytotoxicity than chLym-1 and murine Lym-1, respectively. Used as a pretreatment, chLym-1/IL-2 enhances the uptake of chLym-1 at the tumor site by altering the permeability of tumor vessels producing tumor:normal organ ratios of 420:1 for blood and 1708:1 for muscle at 3 days. The in vitro and in vivo activities of chLym-1/IL-2, therefore, suggest that this genetically engineered antibody fusion protein may represent a new immunotherapeutic reagent for the treatment of human malignant lymphomas.
一种鼠抗人B细胞单克隆抗体Lym-1在治疗人类恶性淋巴瘤方面显示出了巨大的潜力。为了增强其临床应用潜力，对一种由嵌合Lym-1（chLym-1）和白细胞介素2（IL-2）组成的基因工程融合蛋白进行了测试，以评估其在人类恶性淋巴瘤中介导细胞毒性、增加血管通透性以及增强抗体摄取的能力。chLym-1/IL-2融合蛋白最初在杆状病毒系统中表达，最近又在谷氨酰胺合成酶基因扩增系统中表达，结果表明它能够被加工并组装成正常的免疫球蛋白单体，每个抗体带有两个IL-2分子。研究发现，它在抗原结合特异性和相对亲和力方面与chLym-1抗体相当。此外，正如T细胞增殖所证实的那样，它保持了IL-2细胞因子的活性。而且，在针对Raji靶细胞的抗体依赖性细胞毒性试验中，chLym-1/IL-2的细胞毒性分别比chLym-1和鼠Lym-1高约2倍和4倍。作为预处理，chLym-1/IL-2通过改变肿瘤血管的通透性，在3天时使肿瘤与正常器官的血液比例达到420:1，肌肉比例达到1708:1，从而增强了chLym-1在肿瘤部位的摄取。因此，chLym-1/IL-2的体外和体内活性表明，这种基因工程抗体融合蛋白可能代表一种治疗人类恶性淋巴瘤的新型免疫治疗试剂。
